2-imino-1,3-thiazine derivatives

ABSTRACT

The present invention relates to 2-imino-1,3-thiazine derivatives, in specific, 2-imino-1,3-thiazine derivatives having a selective antagonistic activity or agonistic activity to a cannabinoid type 2 receptor and their pharmaceutical use.

This application is a divisional of Ser. No. 10/069,421, filed Feb. 26,2002, now U.S. Pat. No. 6,818,640, which is a 371 U.S. national stage ofInternational Application No. PCT/JP00/06185 filed Sep. 11, 2000.

TECHNICAL FIELD

The present invention relates to 2-imino-1,3-thiazine derivatives, indetail, 2-imino-1,3-thiazine derivatives having a selective antagonisticactivity or agonistic activity to a cannabinoid type 2 receptor andpharmaceutical use of themselves.

BACKGROUND ART

Cannabinoid was discovered as the main active substance contained inmarijuana in 1960 and found to exhibit an activity to the centralnervous system (illusion, euphoria, sensory confusion of time and space)and an activity to the peripheral cell system (immunosuppressiveactivity, anti-inflammatory activity, analgesic activity).

After that, anandamide and 2-arachidonoylglycerol produced fromphospholipid containing arachidonic acid were discovered as endogenousagonists to a cannabinoid receptor. These endogenous agonists were knownto exhibit an activity to the central nervous system and an activity tothe peripheral cell system. It was disclosed in Hypertension (1997) 29,1204–1210 that anandamide exhibits an activity to the cardiovascularsystem.

A cannabinoid type 1 receptor discovered in 1990 was found to distributein the central nervous system such as the brain. Agonists to thisreceptor were found to suppress the release of neurotransmitters tocause central actions such as illusion or the like. A cannabinoid type 2receptor discovered in 1993 was found to distribute in immune tissuessuch as the spleen or the like. Agonists to this receptor were found tosuppress an activation of cells in immunocyte or phlogocyte to exhibitan immunosuppressive activity, an anti-inflammatory activity and ananalgesic activity (Nature, 1993, 365, 61–65).

Therefore, selective antagonists or agonists to the cannabinoid type 2receptor are expected as immunosuppressive agents, anti-inflammatoryagents, analgesic agents without causing side effects on the centralnervous system such as illusion or the drug dependence, which areassociated with the cannabinoid type 1 receptor (Nature, 1998, 349,277–281).

Known as compounds having an antagonistic activity or agonistic activityto the cannabinoid type 2 receptor are isoindolynone derivatives(WO97/29079 and WO99/02499), pyrazole derivatives (WO98/41519) and thelike.

On the other hand, Japanese Patent Publications (Kokai 1986-65894, Kokai1987-29594) disclose that organophosphorus compounds having a2-imino-1,3-thiazine skelton are useful as insecticides.

However, it is not known that 2-imino-1,3-thiazine derivatives have anantagonistic activity or agonistic activity to the cannabinoid type 2receptor.

DISCLOSURE OF INVENTION

The present invention provides 2-imino-1,3-thiazine derivatives or thelike as novel compounds having a selective antagonistic activity oragonistic activity to the cannabinoid type 2 receptor.

The present invention comprises,

-   1) a pharmaceutical composition which comprises a compound of the    formula (I):

wherein R¹ is optionally substituted alkylene, R² is alkyl; a group ofthe formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, and R⁶ is alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substitutedaralkyloxy, optionally substituted aralkylthio, optionally substitutedaralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substitutedaminoalkyl; or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl,optionally substituted amino, optionally substituted aryl or optionallysubstituted heteroaryl, m is an integer of 0 to 2, A is optionallysubstituted aromatic carbocycle or optionally substituted aromaticheterocycle, a prodrug of itself, a pharmaceutically acceptable saltthereof or a solvate thereof,

-   2) the pharmaceutical composition according to the above 1) wherein    the group of the formula:

is a group of the formula:

wherein R³ and R⁴ each is independently hydrogen, alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substituted aryl,optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro,haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy,alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy,alkylthioalkoxy, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, alkoxyiminoalkyl or a groupof the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl,optionally substituted aryl or optionally substituted non-aromaticheterocyclic group,

-   or R³ and R⁴ taken together may form alkylenedioxy, A is optionally    substituted aromatic carbocycle or optionally substituted aromatic    heterocycle,-   3) the pharmaceutical composition according to the above 1) or 2)    which has a binding activity to a cannabinoid type 2 receptor,-   4) the pharmaceutical composition according to the above 3) which    has an agonistic activity to a cannabinoid type 2 receptor,-   5) the pharmaceutical composition according to the above 3) which is    useful as an anti-inflammatory agent,-   6) the pharmaceutical composition according to the above 3) which is    useful as an immunosuppressive agent,-   7) the pharmaceutical composition according to the above 3) which is    useful as a nephritis treating agent,-   8) a compound of the formula (II):

wherein R¹ is optionally substituted alkylene, R² is a group of theformula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substitutedaralkyloxy, optionally substituted aralkylthio, optionally substitutedaralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substitutedaminoalkyl, or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl,optionally substituted amino, optionally substituted aryl or optionallysubstituted heteroaryl, R³ and R⁴ each is independently hydrogen, alkyl,alkoxy, alkylthio, optionally substituted amino, optionally substitutedaryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy,nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy,alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy,alkylthioalkoxy, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or agroup of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl,optionally substituted aryl or optionally substituted non-aromaticheterocyclic group, or

-   R³ and R⁴ taken together may form alkylenedioxy, m is an integer of    0 to 2, A is optionally substituted aromatic carbocycle or    optionally substituted aromatic heterocycle, a prodrug of itself, a    pharmaceutically acceptable salt thereof or a solvate thereof,-   9) the compound according to the above 8) wherein m is 0, a prodrug    of itself, a pharmaceutically acceptable salt thereof or a solvate    thereof,-   10) the compound according to the above 8) or 9) wherein R¹ is a    C2–C9 straight or branched alkylene optionally substituted with    alkylene, a prodrug of itself, a pharmaceutically acceptable salt    thereof or a solvate thereof,-   11) the compound according to any one of the above 8) to 10) wherein    R¹ is a C2–C9 straight alkylene substituted with alkylene, or a    C2–C9 branched alkylene, a prodrug of itself, a pharmaceutically    acceptable salt thereof or a solvate thereof,-   12) the compound according to any one of the above 8) to 11) wherein    R⁶ is alkoxy or alkylthio, and R⁷ is optionally substituted aryl, a    prodrug of itself, a pharmaceutically acceptable salt thereof or a    solvate thereof,-   13) the compound according to any one of the above 8) to 12) wherein    R³ and R⁴ each is independently hydrogen, alkyl, alkoxy or    alkylthio, and A is optionally substituted aromatic carbocycle, a    prodrug of itself, a pharmaceutically acceptable salt thereof or a    solvate thereof,-   14) the compound according to the above 8) wherein R¹ is    2,2-dimethyltrimethylene, 2,2-diethyltrimethylene,    2,2-ethylenetrimethylene, 1-methyltrimethylene,    2-methyltrimethylene, trimethylene, 2,2-di-n-propyltrimethylene,    2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene,    1,1-dimethylethylene or 1-methylethylene, R⁶ is methyl, ethyl,    n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,    methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio,    sec-butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl,    methylthiomethyl, ethylthiomethyl or ethylamino, R⁷ is methyl,    ethyl, 4-tolyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl,    4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl,    R³ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,    sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,    methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino,    acetylamino, N-acetylmethylamino, diethylamino, ethylmethylamino,    propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro,    trifluoromethyl, difluoromethoxy, trifluoromethoxy,    N-methylcarbamoyl, methoxycarbonyl, methanesulfinyl, ethanesulfinyl,    methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl,    1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino,    2-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl, R⁴ is    hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy,    or-   R³ and R⁴ taken together may form —O—CH₂—O—, A is benzene,    naphthalene, pyridine or quinoline, a prodrug of itself, a    pharmaceutically acceptable salt thereof or a solvate thereof,-   15) a pharmaceutical composition which comprises the compound    according to any one of the above 8) to 14), a prodrug of itself, a    pharmaceutically acceptable salt thereof or a solvate thereof,-   16) the pharmaceutical composition according to the above 15) which    has a binding activity to a cannabinoid type 2 receptor,-   17) the pharmaceutical composition according to the above 16) which    has an agonistic activity to a cannabinoid type 2 receptor,-   18) the pharmaceutical composition according to the above 16) which    is useful as an anti-inflammatory agent,-   19) the pharmaceutical composition according to the above 16) which    is useful as an immunosuppressive agent,-   20) the pharmaceutical composition according to the above 16) which    is useful as a nephritis treating agent,-   21) a method for treating inflammation which comprises administering    the pharmaceutical composition according to the above 1),-   22) a method of immunosuppression which comprises administering the    pharmaceutical composition according to the above 1),-   23) a method for treating nephritis which comprises administering    the pharmaceutical composition according to the above 1),-   24) use of the compound according to the above 1) for manufacturing    an anti-inflammatory agent,-   25) use of the compound according to the above 1) for manufacturing    an immunosuppressive agent, and-   26) use of the compound according to the above 1) for manufacturing    a nephritis treating agent.

BEST MODE FOR CARRYING OUT THE INVENTION

The meanings of each term used in compound of the formula (I) and (II)are explained below. Each term is used to express the same meaning inthe specification.

The term “alkylene” includes a C2–C10 straight or branched alkylene, forexample, ethylene, 1-methylethylene, 1-ethylethylene,1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene,1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene,1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene,1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene,2-ethyltrimethylene, 1,1-diethyltrimethylene, 1,2-diethyltrimethylene,2,2-diethyltrimethylene, 2-ethyl-2-methyltrimethylene, tetramethylene,1-methyltetramethylene, 2-methyltetramethylene,1,1-dimethyltetramethylene, 1,2-dimethyltetramethylene,2,2-dimethyltetramethylene, 2,2-di-n-propyltrimethylene or the like.Preferred is a C2–C9 straight or branched alkylene. More preferred is aC2–C9 branched alkylene, for example, 2,2-dimethyltrimethylene,2,2-diethyltrimethylene, 1-methyltrimethylene, 2-methyltrimethylene,trimethylene, 2,2-di-n-propyltrimethylene, 1,1-dimethylethylene or1-methylethylene. The position number of these substituents is based oneither the order of N—R¹—S or that of S—R¹—N.

Examples of substituents of “optionally substituted alkylene” includealkylene (e.g., methylene, ethylene, trimethylene, tetramethylene,pentamethylene or the like), cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or the like), alkoxy (e.g., methoxy, ethoxy orthe like), alkylthio (e.g., methylthio, ethylthio or the like),alkylamino (e.g., methylamino, ethylamino, dimethylamino or the like),acylamino (e.g., acetylamino or the like), aryl (e.g., phenyl or thelike), aryloxy(e.g., phenoxy or the like), halogen (fluoro, chloro,bromo, iodo), hydroxy, amino, nitro, alkylsulfonyl (e.g.,methanesulfonyl, ethanesulfonyl or the like), arylsulfonyl (e.g.,benzenesulfonyl or the like), cyano, hydroxyamino, carboxy,alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or the like), acyl(e.g., acetyl, benzoyl or the like), aralkyl (e.g., benzyl or the like),mercapto, hydorazino, amidino, guanidino or the like. One to four ofthese substituents may substitute at any position. Preferred as thesubstituent of “optionally substituted alkylene” is alkylene.

Alkylene substituted with alkylene include alkylene substituted via aspiro atom with alkylene (e.g., 2,2-ethylenetrimethylene,2,2-trimethylenetrimethylene, 2,2-tetramethylenetrimethylene,2,2-pentamethylenetrimethylene or the like) and alkylene substituted atthe different positions with alkylene (e.g., 1,2-tetramethyleneethylene,1,2-ethylenetrimethylene or the like). Preferred examples include2,2-ethylenetrimethylene, 2,2-trimethylenetrimethylene,2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene,especially, 2,2-ethylenetrimethylene, 2,2-tetramethylenetrimethylene and2,2-pentamethylenetrimethylene.

The term “alkyl” includes a C1–C10 straight or branched alkyl, forexample, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl,n-noyl, n-decyl or the like. Preferred is a C1–C4 straight or branchedalkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl and tert-butyl.

The term “alkoxy” includes an oxygen atom substituted with the above“alkyl”, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy,n-octyloxy or the like. Preferred is a C1–C4 straight or branchedalkoxy, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, sec-butoxy and tert-butoxy.

The term “alkylthio” includes a sulfur atom substituted with the above“alkyl”, for example, methylthio, ethylthio, n-propylthio, i-propylthio,n-butylthio, i-butylthio, sec-butylthio, tert-butylthio, n-pentylthio,n-hexylthio or the like. Preferred is a C1–C4 straight or branchedalkylthio, for example, methylthio, ethylthio, n-propylthio,i-propylthio, n-butylthio, i-butylthio, sec-butylthio andtert-butylthio.

Examples of substituents of “optionally substituted amino” includesalkyl (e.g., methyl, ethyl, n-propyl, i-propyl or the like), acyl (e.g.,formyl, acetyl, propionyl, benzoyl or the like) or the like. A nitrogenatom of an amino group may be mono- or di-substituted with thesesubstituents.

Examples of “optionally substituted amino” include amino, methylamino,ethylamino, n-propylamino, i-propylamino, dimethylamino, diethylamino,ethylmethylamino, acetylamino, N-acetylmethylamino, propylmethylamino orthe like.

The term “aryl” includes a C6–C14 aromatic carbocyclic group, forexample, phenyl, naphthyl, anthryl, phenanthryl or the like.

The term “aralkyl” includes the above “alkyl” substituted with the above“aryl”, for example, benzyl, phenylethyl (e.g., 1-phenylethyl,2-phenylethyl), phenylpropyl (e.g., 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl or the like), naphthylmethyl (e.g., 1-naphthylmethyl,2-naphthylmethyl or the like) or the like.

The term “aralkyloxy” includes an oxygen atom substituted with the above“aralkyl”, for example, benzyloxy, phenylethyloxy (e.g.,1-phenylethyloxy, 2-phenylethyloxy), phenylpropoxy (e.g.,1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy or the like),naphthylmethoxy (e.g., 1-naphthylmethoxy, 2-naphthylmethoxy or the like)or the like.

The term “aralkylthio” includes a sulfur atom substituted with the above“aralkyl”, for example, benzylthio, phenylethylthio (e.g.,1-phenylethylthio, 2-phenylethylthio), phenylpropylthio (e.g.,1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio or the like),naphthylmethylthio (e.g., 1-naphthylmethylthio, 2-naphthylmethylthio orthe like) or the like.

The term “aralkylamino” includes a nitrogen atom substituted with one ortwo of the above “aralkyl”, for example, benzylamino, phenylethylamino(e.g., 1-phenylethylamino, 2-phenylethylamino), phenylpropylamino (e.g.,1-phenylpropylamino, 2-phenylpropylamino, 3-phenylpropylamino),naphthylmethylamino (e.g., 1-naphthylmethylamino, 2-naphthylmethylaminoor the like), dibenzylamino or the like.

The term “alkoxyalkyl” includes the above “alkyl” substituted with theabove “alkoxy”, for example, methoxymethyl, ethoxymethyl,n-propoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl,2-ethoxyethyl, 1-n-propoxyethyl, 2-n-propoxyethyl, 1-methoxy-n-propyl,2-methoxy-n-propyl, 3-methoxy-n-propyl, 1-ethoxy-n-propyl,2-ethoxy-n-propyl, 3-ethoxy-n-propyl, 1-n-propoxy-n-propyl,2-n-propoxy-n-propyl, 3-n-propoxy-n-propyl or the like.

The term “alkylthioalkyl” includes the above “alkyl” substituted withthe above “alkylthio”, for example, methylthiomethyl, ethylthiomethyl,n-propylthiomethyl, 1-methylthioethyl, 2-methylthioethyl,1-ethylthioethyl, 2-ethylthioethyl, 1-n-propylthioethyl,2-n-propylthioethyl, 3-n-propylthioethyl, 1-methylthio-n-propyl,2-methylthio-n-propyl, 3-methylthio-n-propyl, 1-ethylthio-n-propyl,2-ethylthio-n-propyl, 3-ethylthio-n-propyl, 1-n-propylthio-n-propyl,2-n-propylthio-n-propyl, 3-n-propylthio-n-propyl or the like.

The term “optionally substituted aminoalkyl” includes the above “alkyl”substituted with the above “optionally substituted amino”, for example,N-methylaminomethyl, N-acetylaminomethyl, N,N-dimethylaminomethyl or thelike.

The term “alkoxyalkoxy” includes the above “alkoxy” substituted with theabove “alkoxy”, for example, methoxymethoxy, ethoxymethoxy,n-propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy orthe like.

The term “alkylthioalkoxy” includes the above “alkoxy” substituted withthe above “alkylthio”, for example, methylthiomethoxy, ethylthiomethoxy,n-propylthiomethoxy, isopropylthiomethoxy, 1-methylthioethoxy,2-methoxyethoxy or the like.

The term “heteroaryl” includes a C1–C9 heteroaryl having one to fournitrogen atom(s), oxygen atom(s) and/or sulfur atom(s), for example,furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl,2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl,5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g.,3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g.,1,3,4-oxadiazol-2-yl), benzofuryl (e.g., 2-benzo[b]furyl,3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl,7-benzo[b]furyl), benzothienyl (e.g., 2-benzo[b]thienyl,3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl,6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (e.g.,1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl),dibenzofuryl, benzoxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl,5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl,4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl),quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl,6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl (e.g.,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl,8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl,6-phthalazinyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl,8-isoquinolyl), puryl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl,6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl(e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl),indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), isoindolyl, phenazinyl (e.g., 1-phenazinyl,2-phenazinyl) or phenothiadinyl (e.g., 1-phenothiadinyl,2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl) or the like.

Preferred as heteroaryl of R³ and R⁴ is 3-pyridyl. Preferred asheteroaryl of R⁷ is 2-thienyl.

The ring A includes “optionally substituted aromatic carbocycle” or“optionally substituted aromatic heterocycle”.

The term “aromatic carbocycle” includes a C6–C14 aromatic carbocycle,for example, benzene, naphthalene, anthracene, phenanthrene or the like.Preferred is benzene or naphthalene.

The term “aromatic heterocycle” includes a C1–C9 aromatic ring havingone to four nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s), forexample, furan, thiophene, pyrrole, imidazole, pyrazole, triazole,tetrazole, oxazole, isoxazole, thiazole, thiadiazole, isothiazole,pyridine, pyridazine, pyrimidine, furazan, pyrazine, benzofuran,benzothiophene, benzimidazole, dibenzofuran, benzoxazole, quinoxaline,cinnoline, quinazoline, quinoline, phthalazine, isoquinoline, purine,pteridine, carbazole, phenanthridine, acridine, indole, isoindole orphenazine or the like. Preferred is pyridine, quinoline or isoquinoline.

Examples of the substituents of “optionally substituted aralkyloxy”,“optionally substituted aralkylthio”, “optionally substitutedaralkylamino”, “optionally substituted aryl”, “optionally substitutedheteroaryl”, “optionally substituted aryloxy”, “optionally substitutedaromatic carbocycle”, “optionally substituted aromatic heterocycle” and“optionally substituted non-aromatic heterocyclic group” include alkyl,alkoxy, alkylthio, optionally substituted amino, optionally substitutedaryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy,nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy,alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy,alkylthioalkoxy, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, alkoxyiminoalkyl, a groupof the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl,optionally substituted aryl or optionally substituted non-aromaticheterocyclic group, arylsulfonyl (e.g., benzenesulfonyl or the like),cyano, hydroxy amino, aralkyl (e.g., benzyl or the like), mercapto,hydrazino, amidino, guanidino, isocyano, isocyanato, thiocyanato,isothiocyanato, sulfamoyl, formyloxy, haloformyl, oxalo, thioformyl,thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino,azido, ureido, amidino, guanidino, oxo, thioxo or the like.

These substituents may substitute at any substitutable positions.Alkylenedioxy may substitute at the same or different positions on thering. An example of alkylenedioxy includes —O—CH₂—O—, —O—CH₂—CH₂—O—,—O—CH₂—CH₂—CH₂—O—.

The term “aryloxy” includes an oxygen atom substituted with the above“aryl”, for example, phenoxy, naphthoxy (e.g., 1-naphthoxy, 2-naphthoxyor the like), anthryloxy (e.g., 1-anthryloxy, 2-anthryloxy or the like),phenanthryl (e.g., 1-phenanthryl, 2-phenanthryl or the like) or thelike.

The term “cycloalkyl” includes C3–C7 cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

The term “halogen” includes fluoro, chloro, bromo and iodo. Preferred isfluoro, chloro or bromo.

The term “haloalkyl” includes the above “alkyl” substituted with one ormore halogen, for example, chloromethyl, dichloromethyl, difluoromethyl,trifluoromethyl, chloroethyl (e.g., 1-chloroethyl, 2-chloroethyl or thelike), dichloroethyl (e.g., 1,1-dichloroethyl, 1,2-dichloroethyl,2,2-dichloroethyl or the like) or the like.

The term “haloalkoxy” includes the above “alkoxy” substituted with oneor more halogen, for example, dichloromethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy (2,2,2-trifluoroethoxy or the like) orthe like.

Examples of the substituents of “optionally substituted carbamoyl”include alkyl (e.g., methyl, ethyl, n-propyl, i-propyl or the like),acyl (e.g., formyl, acetyl, propionyl, benzoyl or the like) or the like.The nitrogen atom of carbamoyl group may be mono- or di-substituted withthese substituents.

Preferred as “optionally substituted carbamoyl” is carbamoyl,N-methylcarbamoyl or N-ethylcarbamoyl.

The term “alkoxycarbonyl” includes carbonyl substituted with “alkoxy”.Preferred is methoxycarbonyl, ethoxycarbonyl or the like.

The term “alkylsulfinyl” includes sulfinyl substituted with the above“alkyl”. Preferred is methanesulfinyl, ethanesulfinyl or the like.

The term “alkylsulfonyl” includes sulfonyl substituted with the above“alkyl”. Preferred is methanesulfonyl, ethanesulfonyl or the like.

The term “non-aromatic heterocyclic group” includes a C1–C9 non-aromaticring having one to four nitrogen atom(s), oxygen atom(s) and/or sulfuratom(s), for example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl,2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl,4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino,2-piperidyl, 3-piperidyl, 4-piperidyl, piperazino, 2-piperazinyl,2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl or the like.Preferred is morpholino, pyrrolidino, piperidino or piperazino.

The term “alkoxyiminoalkyl” include the above “alkyl” substituted withalkoxyimino, for example, methoxyiminomethyl, ethoxyiminomethyl,1-methoxyiminoethyl or the like.

Examples of a group of the formula: —C(═O)—R^(H) wherein R^(H) ishydrogen, alkyl, optionally substituted aryl or optionally substitutednon-aromatic heterocyclic group include formyl, acetyl, benzoyl,toluoyl, morpholinocarbonyl or the like.

The term “m” is an integer of 0 to 2. Preferred as “m” is 0.

The term “an agonistic activity to a cannabinoid type 2 receptor”includes agonizing a cannabinoid type 2 receptor.

The compounds of the present invention can be prepared in accordancewith the following processes.

wherein R¹ is optionally substituted alkylene, R² is alkyl; a group ofthe formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substitutedaralkyloxy, optionally substituted aralkylthio, optionally substitutedaralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substitutedaminoalkyl; or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl,optionally substituted amino, optionally substituted aryl or optionallysubstituted heteroaryl, R³ and R⁴ each is independently hydrogen, alkyl,alkoxy, alkylthio, optionally substituted amino, optionally substitutedaryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy,nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy,alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy,alkylthioalkoxy, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or agroup of the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl,optionally substituted aryl or optionally substituted non-aromaticheterocyclic group, or

-   R³ and R⁴ taken together may form —O—CH₂—O—, m is an integer of 0 to    2, A is optionally substituted aromatic carbocycle or optionally    substituted aromatic heterocycle.    Process 1

This is a process for producing a compound of the formula (IV) whichcomprises converting amino group of a compound of the formula (III) toisothiocyanic acid ester (isothiocyanate).

A method for converting amino group to isothio cyanic acid ester(isothiocyanate) includes the following methods; 1) a method whichcomprises reacting the starting compound with carbon disulfide in thepresence of a base such as ammonia (NH₃, NH₄OH), triethylamine (Et₃N)and reacting the obtained dithiocarbamate with ethyl chlorocarboxylate(ClCO₂Et) and triethylamine (Et₃N), 2) a method which comprises reactingthe above dithiocarbamate with acid metalate such as lead nitrate or thelike, 3) a method of reacting thiophosgene (CSCl₂) and 4) a method ofreacting thiocarbonyldiimidazole or the like.

In the above 1), a base (1.0 to 1.5 mole equivalent) and carbondisulfide (1.0 to 1.5 mole equivalent) are added to a solution of acompound of the formula (III) in an aprotic solvent (e.g., diethylether,tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane,chloroform or the like) and the mixture is stirred for 0.5 to 10 hours.After that, ethyl chlorocarboxylate (1.0 to 1.5 mole equivalent) andtriethylamine (1.0 to 1.5 mole equivalent) are added thereto and themixture is stirred in the same solvent for 0.5 to 10 hours. The reactiontemperature is preferably 0 to 100° C., especially 0° C. to roomtemperature.

In the above 3), thiophosgene (1.0 to 1.5 mole equivalent) is added to asolution of the compound of the formula (III) in an aprotic solvent(e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene,toluene, dichloromethane, chloroform or the like) and stirred for 0.5 to10 hours. The reaction temperature is preferably 0 to 100° C.,especially 0° C. to room temperature.

In the above 4), thiocarbonyldiimidazole (1.0 to 1.5 mole equivalent) isadded to a solution of the compound of the formula (III) in an aproticsolvent (e.g., diethylether, tetrahydrofuran, dimethylformamide,benzene, toluene, dichloromethane, chloroform or the like) and stirredfor 0.5 to 10 hours. The reaction temperature is preferably 0 to 100°C., especially 0° C. to room temperature.

Examples of the compound of the formula (III) wherein m is 0 includeaniline, 2-methylaniline, 2-ethylaniline, 2-n-propylaniline,2-i-propylaniline, 2-n-butylaniline, 2-sec-butylaniline,2-t-butylaniline, 3-methylaniline, 3-i-propylaniline,3-i-propyl-4-methylaniline, 3-t-butylaniline, 4-methylaniline,4-i-propylaniline, 2,6-dimethylaniline, 2,3-dimethylaniline,2,4-dimethylaniline, 3,4-diethylaniline, 2,5-dimethylaniline,3,4-dimethylaniline, 3,5-dimethylaniline, 2,6-diethylaniline,2,6-di-i-propylaniline, 2-methoxyaniline, 2-ethoxyaniline,2-i-propoxyaniline, 3-methoxyaniline, 3,5-dimethoxyaniline,3-n-butoxyaniline, 4-n-butoxyaniline, 4-ethoxyaniline,3,4-dimethoxyaniline, 2-methylthioaniline, 2-ethylthioaniline,2-i-propylthioaniline, 2-N,N-dimethylaminoaniline, 2-phenylaniline,3-phenylaniline, 4-phenoxyaniline, 2-cyclohexylaniline,2-cyclopentylaniline, 2-nitroaniline, 2,4-dinitroaniline,2-fluoroaniline, 2-chloroaniline, 4-chloroaniline, 2,3-dichloroaniline,3,4-dichloroaniline, 2-i-propyl-4-nitroaniline,2-i-propyl-6-nitroaniline, 2-hydroxyaniline,2-N,N-dimethylaminocarbonylaniline, 2-N-acetylaniline,2-(1-ethylpropyl)aniline, 2-i-propyl4-methylaniline,2-i-propyl-4-hydroxyaniline, 2-i-propyl-4-chloroaniline,2-i-propyl-4-aminoaniline, 2-i-propyl-5-methylaniline,2-i-propyl-5-hydroxy aniline, 2-i-propyl-5-chloroaniline,4-chloro-3-methylaniline, 3,4-methylenedioxyaniline or the like.

Examples of the compound of the formula (III) wherein m is 1 includebenzylamine, 2-methylbenzylamine, 2-ethylbenzylamine,2-n-propylbenzylamine, 2-i-propylbenzylamine, 2-n-butylbenzylamine,2-sec-butylbenzylamine, 2-t-butylbenzylamine, 3-methylbenzylamine,3-i-propylbenzylamine, 3-i-propyl-4-methylbenzylamine,3-t-butylbenzylamine, 4-methylbenzylamine, 4-i-propylbenzylamine,2,6-dimethylbenzylamine, 2,3-dimethylbenzylamine,2,4-dimethylbenzylamine, 3,4-diethylbenzylamine,2,5-dimethylbenzylamine, 3,4-dimethylbenzylamine,3,5-dimethylbenzylamine, 2,6-diethylbenzylamine,2,6-di-i-propylbenzylamine, 2-methoxybenzylamine, 2-ethoxybenzylamine,2-i-propoxybenzylamine, 3-methoxybenzylamine, 3,5-dimethoxybenzylamine,3-n-butoxybenzylamine, 4-n-butoxybenzylamine, 4-ethoxybenzylamine,3,4-dimethoxybenzylamine, 2-methylthiobenzylamine,2-ethylthiobenzylamine, 2-i-propylthiobenzylamine,2-N,N-dimethylaminobenzylamine, 2-phenylbenzylamine,3-phenylbenzylamine, 4-phenoxybenzylamine, 2-cyclohexylbenzylamine,2-cyclopentylbenzylamine, 2-nitrobenzylamine, 2,4-dinitrobenzylamine,2-fluorobenzylamine, 2-chlorobenzylamine, 4-chlorobenzylamine,2,3-dichlorobenzylamine, 3,4-dichlorobenzylamine,2-i-propyl-4-nitrobenzylamine, 2-i-propyl-6-nitrobenzylamine,2-hydroxybenzylamine, 2-N,N-dimethylaminocarbonylbenzylamine,2-N-acetylbenzylamine, 2-(1-ethylpropyl)benzylamine,2-i-propyl4-methylbenzylamine, 2-i-propyl-4-hydroxybenzylamine,2-i-propyl-4-chlorobenzylamine, 2-i-propyl-4-aminobenzylamine,2-i-propyl-5-methylbenzylamine, 2-i-propyl-5-hydroxybenzylamine,2-i-propyl-5-chlorobenzylamine, 4-chloro-3-methylbenzylamine,3,4-methylenedioxybenzylamine or the like.

Examples of the compound of the formula (III) wherein m is 2 includephenethylamine, 2-methylphenethylamine, 2-ethylphenethylamine,2-n-propylphenethylamine, 2-i-propylphenethylamine,2-n-butylphenethylamine, 2-sec-butylphenethylamine,2-t-butylphenethylamine, 3-methylphenethylamine,3-i-propylphenethylamine, 3-i-propyl-4-methylphenethylamine,3-t-butylphenethylamine, 4-methylphenethylamine,4-i-propylphenethylamine, 2,6-dimethylphenethylamine,2,3-dimethylphenethylamine, 2,4-dimethylphenethylamine,3,4-diethylphenethylamine, 2,5-dimethylphenethylamine,3,4-dimethylphenethylamine, 3,5-dimethylphenethylamine,2,6-diethylphenethylamine, 2,6-di-i-propylphenethylamine,2-methoxyphenethylamine, 2-ethoxyphenethylamine,2-i-propoxyphenethylamine, 3-methoxyphenethylamine,3,5-dimethoxyphenethylamine, 3-n-butoxyphenethylamine,4-n-butoxyphenethylamine, 4-ethoxyphenethylamine,3,4-dimethoxyphenethylamine, 2-methylthiophenethylamine,2-ethylthiophenethylamine, 2-i-propylthiophenethylamine,2-N,N-dimethylaminophenethylamine, 2-phenylphenethylamine,3-phenylphenethylamine, 4-phenoxyphenethylamine,2-cyclohexylphenethylamine, 2-cyclopentylphenethylamine,2-nitrophenethylamine, 2,4-dinitrophenethylamine,2-fluorophenethylamine, 2-chlorophenethylamine, 4-chlorophenethylamine,2,3-dichlorophenethylamine, 3,4-dichlorophenethylamine,2-i-propyl-4-nitrophenethylamine, 2-i-propyl-6-nitrophenethylamine,2-hydroxyphenethylamine, 2-N,N-dimethylaminocarbonylphenethylamine,2-N-acetylphenethylamine, 2-(1-ethylpropyl)phenethylamine,2-i-propyl4-methylphenethylamine, 2-i-propyl-4-hydroxyphenethylamine,2-i-propyl-4-chlorophenethylamine, 2-i-propyl-4-aminophenethylamine,2-i-propyl-5-methylphenethylamine, 2-i-propyl-5-hydroxyphenethylamine,2-i-propyl-5-chlorophenethylamine, 4-chloro-3-methylphenethylamine,3,4-methylenedioxyphenethylamine or the like.

Process 2

This is a process for producing a compound of the formula (V) whichcomprises reacting an isothiocyanate of the compound of the formula (IV)with NH₂—R¹—OH.

This process can be carried out in an aprotic solvent (e.g.,diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene,dichloromethane, chloroform or the like).

The reaction temperature is preferably 0 to 100° C., especially 0° C. toroom temperature. The reaction time is 0.5 to 10 hours.

The amount of NH₂—R¹—OH wherein R¹ is optionally substituted alkylene is1.0 to 1.5 mole equivalent to that of the compound of the formula (IV).

Examples of NH₂—R¹—OH include 2-aminoethanol, 2-amino-2-methylethanol,2-amino-1-methylethanol, 2-amino-1,1-dimethylethanol, 3-aminopropanol,3-amino-2,2-dimethylpropanol, 3-amino-1-methylpropanol,3-amino-2-methylpropanol, 3-amino-3-methylpropanol,3-amino-2,2-diethylpropanol, 1-aminomethyl-1-hydroxymethylcyclopropane,1-aminomethyl-1-(hydroxymethyl)cyclobutane, 2-(aminomethyl)cyclopentanolor the like.

Process 3

This is a process for producing a compound of the formula (VI) whichcomprises the cyclization of the compound of the formula (V).

A method of the cyclization includes 1) a method which comprisesreacting with diethylazodicarboxylate (DEAD) and triphenylphosphine(Ph₃P), 2) a method which comprises reacting with hydrochloric acid orthe like.

In the above 1), the reaction can be carried out in an aprotic solvent(e.g., diethylether, tetrahydrofuran, dimethylformamide, benzene,toluene, dichloromethane, chloroform or the like) with stirring for 0.5to 5 hours at 0° C. to room temperature. The amount ofdiethylazodicarboxylate (DEAD) and triphenylphosphine (Ph₃P) are 1.0 to1.5 mole equivalent to that of the compound (V).

In the above 2), the reaction can be carried out in concentratedhydrochloric acid with refluxing for 0.5 to 10 hours.

Process 4

This is a process for producing a compound of the formula (II) whichcomprises introducing R² (a group of the formula: —C(═R⁵)—R⁶ or a groupof the formula: —SO₂R⁷ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substitutedaralkyloxy, optionally substituted aralkylthio, optionally substitutedaralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substitutedaminoalkyl, R⁷ is alkyl, optionally substituted amino, optionallysubstituted aryl or optionally substituted heteroaryl, to the compoundof the formula (VI).

This process can be carried out by reacting with a compound of theformula: X—C(═R⁵)—R⁶ wherein R⁵ and R⁶ are as defined above and X ishalogen in the presence of a base (e.g., triethylamine, pyridine,N,N-dimethylaminopyridine or the like). This process can be carried outunder generally known conditions of N-acylation. For example, thereaction can be carried out in an aprotic solvent (e.g., diethylether,tetrahydrofuran, dimethylformamide, benzene, toluene, dichloromethane,chloroform or the like) with stirring at 0 to 100° C. for 0.5 to 10hours.

A thioic acid ester, a compound wherein R⁵ is S, R⁶ is alkylthio oroptionally substituted aralkylthio can be prepared by reacting withcarbon dioxide (CS₂) in the presence of a base (e.g., sodium hydride orthe like), and reacting with halogenated alkyl (e.g., methyl iodide,ethyl iodide or the like) or halogenated aralkyl (e.g., benzylbromide orthe like). The reaction can be carried out in an aprotic solvent (e.g.,diethylether, tetrahydrofuran, dimethylformamide, benzene, toluene,dichloromethane, chloroform or the like) with stirring at 0° C. to roomtemperature.

When R² to be introduced is a group of the formula: —SO₂R⁷ wherein R⁷ isalkyl, optionally substituted amino, optionally substituted aryl oroptionally substituted heteroaryl, the compound of the formula (VI) canbe reacted with a compound of the formula: R⁷SO₂X wherein X is halogenor the like in the presence of a base.

A prodrug is a derivative which is converted to a pharmaceuticallyactive compound of the present invention under a physiologicalcondition. Method for the selection and process of an appropriateprodrug derivative are described in the literature such as Design ofProdrugs, Elsevier, Amsterdam 1985.

A prodrug of the present invention can be prepared by introducing aleaving group to substituents on ring A which are substitutable (e.g.,amino, hydroxy or the like). Examples of a prodrug derived form acompound having an amino group includes carbamate derivatives (e.g.,methylcarbamate, cyclopropylmethylcarbamate, t-butylcarbamate,benzylcarbamate or the like), amide derivatives (e.g., formamide,acetamide or the like), N-alkyl derivative (e.g., N-allylamine,N-methoxymethylamine or the like) or the like. Examples of a prodrugderived form a compound having hydroxy group include ether derivatives(methoxymethylether, methoxyethoxymethylether or the like), esterderivatives (e.g., acetate, pivaloate, benzoate or the like) or thelike.

Examples of a pharmaceutically acceptable salt include basic salts(e.g., alkali metal salts such as sodium or potassium salts;alkaline-earth metal salts such as calcium or magnesium salts; ammoniumsalts; aliphatic amine salts such as trimethylamine, triethylamine,dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine orprocaine salts; aralkyl amine salts such as N,N-dibenzylethylenediaminesalts; heterocyclic aromatic amine salts such as pyridine salts,picoline salts, quinoline salts or isoquinoline salts; quaternaryammonium salts such as tetramethylammonium salts, tetraethylammoniumsalts, benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts such as argininesalts or lysine salts). Acid addition salts include, for example,mineral acid salts such as hydrochlorides salts, sulfates salts, nitratesalts, phosphates salts, carbonates salts, hydrogen carbonates salts orperchlorates salts; organic acid salts such as acetates, propionates,lactates, maleates, fumarates, tartrates, malates, succinates, orascorbates; sulfonates such as methanesulfonates, isethionates,benzenesulfonates, or p-toluenesulfonates; and acidic amino acid saltssuch as aspartates or glutamates.

A solvate includes a solvate of the compound of the formula (I) or (II),a prodrug of itself or a pharmaceutically acceptable salt thereof, forexample, monosolvate, disolvate, monohydrate, dihydrate or the like.

The compound of the present invention has a binding activity to thecannabinoid type 2 receptor (CB2R), and selectively binds to thecannabinoid type 2 receptor (CB2R) to exhibit an antagonistic activityor agonistic activity to CB2R, especially an agonistic activity to CB2R.

Since the compound of the present invention does not have a bindingactivity to the cannabinoid type 1 receptor (CB1R), the present compoundneither causes side effects on the central nervous system such asillusion or the drug dependence associated with the cannabinoid type 1receptor.

Therefore, the compound of the present invention can be used fortreating or preventing diseases associated with the cannabinoid type 2receptor (CB2R). For example, Proc. Natl. Acad. Sci. USA 96,14228–14233. discloses that CB2R agonists have an anti-inflammatoryactivity and analgesic activity. Nature, 1998, 349, 277–281 disclosesthat CB2R agonists have an analgesic activity. European Journal ofPharmacology 396 (2000) 85–92 discloses that CB2R antagonists have ananalgesic activity.

The compound of the present invention suppresses an activation of cellsin immunocyte or phlogocyte to exhibit an activity to the peripheralcell system (e.g., an immunosuppressive activity, an anti-inflammatoryactivity and an analgesic activity). Thus, the present compounds can beused as anti-inflammatory agents, antiallergenic agents, analgesicagents, immune deficiency treating agents, immunosuppressive agents,immunomodulating agents, autoimmune disease treating agents, chronicrheumatoid arthritis treating agents, multiple sclerosis treating agentsor the like.

Agonists to the cannabinoid type 2 receptor are known to suppressnephritis caused by rat Thy-1 antibody in WO97/29079. Therefore, thepresent compounds are useful as nephritis treating agents.

When using a compound of the present invention in treatment, it can beformulated into ordinary formulations for oral and parenteraladministration. A pharmaceutical composition containing a compound ofthe present invention can be in the form for oral and parenteraladministration. Specifically, it can be formulated into formulations fororal administration such as tablets, capsules, granules, powders, syrup,and the like; those for parenteral administration such as injectablesolution or suspension for intravenous, intramuscular or subcutaneousinjection, inhalant, eye drops, nasal drops, suppositories, orpercutaneous formulations such as ointment.

In preparing the formulations, carriers, excipients, solvents and basesknown to one ordinary skilled in the art may be used. Tablets areprepared by compressing or formulating an active ingredient togetherwith auxiliary components. Examples of usable auxiliary componentsinclude pharmaceutically acceptable excipients such as binders (e.g.,cornstarch), fillers (e.g., lactose, microcrystalline cellulose),disintegrates (e.g., starch sodium glycolate) or lubricants (e.g.,magnesium stearate). Tablets may be coated appropriately. In the case ofliquid formulations such as syrups, solutions or suspensions, they maycontain suspending agents (e.g., methyl cellulose), emulsifiers (e.g.,lecithin), preservatives and the like. In the case of injectableformulations, it may be in the form of solution or suspension, or oilyor aqueous emulsion, which may contain suspension-stabilizing agent ordispensing agent, and the like. In the case of an inhalant, it isformulated into a liquid formulation applicable to an inhaler. In thecase of eye drops, it is formulated into a solution or a suspension.

Although an appropriate dosage of the present compound varies dependingon the administration route, age, body weight, sex, or conditions of thepatient, and the kind of drug(s) used together, if any, and should bedetermined by the physician in the end, in the case of oraladministration, the daily dosage can generally be between about 0.01–100mg, preferably about 0.01–10 mg, more preferably about 0.01–1 mg, per kgbody weight. In the case of parenteral administration, the daily dosagecan generally be between about 0.001–100 mg, preferably about 0.001–1mg, more preferably about 0.001–0.1 mg, per kg body weight. The dailydosage can be administered in 1–4 divisions.

EXAMPLE

The following Examples are provided to further illustrate the presentinvention and are not to be construed as limiting the scope.

The meaning of each abbreviation are shown as follows.

-   Me: methyl, Et: ethyl, Pr: propyl, Pr^(i): i-propyl,-   Bu: butyl, Bu^(i): i-butyl, Bu^(s): sec-butyl,-   Bu^(t): t-butyl-   Ph: phenyl, Ac: acetyl, Bn: benzyl-   DMF: N,N-dimethylformamide, THF: tetrahydrofuran,-   DEAD: diethyl azodicarboxylate,

Reference Example 1-1 Preparation of (2-isopropylphenyl)isothiocyanate(Compound 2)

To a mixture of 2-isopropylaniline (5.00 g), triethylamine (3.74 g) andtoluene (10 ml) was added dropwise for 10 minutes carbon dioxide (2.81g). The mixture was stirred at room temperature for 1 hour and keptstationary for 12 hours. The reaction mixture was concentrated underreduced pressure. Dichloromethane (20 ml) and triethylamine (3.74 g)were added thereto. To the solution was added under ice-cooling for 10minutes ethyl chlorocarbonate (4.01 g). The mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added 10%hydrochloric acid (20 ml). The mixture was extracted withdichloromethane (60 ml), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to give(2-isopropylphenyl)isothiocyanate (6.55 g, yield: 99%) as yellow oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.25(6H, d, J=6.7), 3.25(1H, q, J=6.7),7.14–7.30(4H, m).

Reference Example 1-2 Preparation of (2-isopropylphenyl)isothiocyanate(Compound 2)

To a solution of 2-isopropylaniline (1.81 g) in diethylether (20 ml) wasadded dropwise under ice-cooling for 10 minutes thiophosgene (1.54 g).The mixture was stirred at room temperature for 1 hour.

To the reaction solution was added water (30 ml). The mixture wasextracted with diethylether (60 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give(2-isopropylphenyl)isothiocyanate (2.35 g, yield: 99%) as brown oil.

Reference Example 2 Preparation ofN-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea(Compound 3)

To a solution of (2-isopropylphenyl)isothiocyanate (3.30 g) indiethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.92 g).The mixture was stirred at room temperature for 1 hour and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane/ethyl acetate) to giveN-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (4.60 g,yield: 88%) as yellow oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 1.25(6H, d, J=6.7), 3.11(1H, q,J=6.7), 3.25(2H, s), 3.55(2H, d, J=6.3), 6.05(1H, m), 7.17–7.40(4H, m).

Reference Example 3 Preparation of2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound 4)

To N-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea(10.37 g) was added concentrated hydrochloric acid (5 ml). The mixturewas refluxed for 3 hours. The reaction solution was cooled to roomtemperature and poured into an aqueous solution of 20% sodium hydroxide(25 ml). The precipitated crystal was filtered and recrystallized withethyl acetate to give2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (4.80 g, yield:50%) as a white crystal.

M.p. 155–157° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.15(6H, s), 1.20(6H, d, J=6.7), 2.67(2H, s),3.09(2H, s), 3.15(1H, q, J=6.7), 6.88(1H, m), 7.05–7.11(2H, m), 7.20(1H,m).

Reference Example 4 Preparation of2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (Compound 4)

To a solution ofN-(2-isopropylphenyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (1.00 g)in tetrahydrofuran (6 ml) was added dropwise thionylchloride (0.60 g).The mixture was stirred at room temperature for 1 hour and concentratedunder reduced pressure. To the solution were added acetonitrile (20 ml)and potassium carbonate (0.93 g). The mixture was refluxed for 2 hours.To the solution was added water (40 ml). The mixture was extracted withdichloromethane (60 ml), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane/ethyl acetate) to give2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.45 g, yield:48%) as a white crystal.

The following Examples 1 to 5 were carried out by using2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine prepared inReference Example 3 and 4.

Example 1 Preparation of3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (CompoundI-1)

To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.26 g) in N,N-dimethylformamide (2 ml) was added under ice-cooling 60%sodium hydride (0.05 g). The mixture was stirred for 30 minutes.Ethyliodide (0.17 g) was added thereto. The mixture was stirred at roomtemperature for 2 hours. To a reaction mixture was added water (30 ml),extracted with diethylether (60 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane/ethylacetate) to give3-ethyl-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.21 g,yield: 71%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.13 (6H, s), 1.20 (6H, d, J=6.9), 1.25 (3H, t,J=7.4), 2.61 (2H, s),3.05 (2H, s), 3.17 (1H, m), 3.64 (2H, q, J=6.9),6.72–6.80 (1H, m), 6.98–7.07 (2H, m), 7.20–7.32 (1H, m).

Example 2 Preparation of2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine(Compound I-2)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was addeddropwise for 5 minutes propionylchloride (0.13 g). The mixture wasstirred at room temperature for 2 hours. To the solution was added water(30 ml). The mixture was extracted with diethylether (60 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give2-(2-isopropylphenyl)imino-3-propionyl-5,5-dimethyl-1,3-thiazine (0.18g, yield: 56%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃)1.14 (6H, s), 1.20 (6H, d, J=6.9), 1.22 (3H, t,J=7.4), 2.60 (2H, s), 2.95 (2H, q, J=7.4), 2.96 (1H, q, J=6.9), 3.73(2H, s), 6.73–6.78 (1H, m), 7.10–7.17 (2H, m), 7.25–7.32 (1H, m).

Example 3 Preparation of3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(Compound I-3)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was addeddropwise for 5 minutes ethyl chlorocarbonate (0.13 g). The mixture wasstirred at room temperature for 2 hours. To the solution was added water(30 ml). The mixture was extracted with diethylether (60 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.23 g, yield: 68%) as a white crystal. M.p. 84–86° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.16 (6H, s), 1.21 (6H, d, J=6.9), 1.36 (3H, t,J=7.1), 2.59 (2H, s), 3.17 (1H, q, J=6.9), 3.65 (2H, s), 4.32 (2H, q,J=7.1), 6.74–6.78 (1H, m), 7.12–7.16 (2H, m), 7.30–7.36 (1H, m).

Example 4 Preparation of3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(Compound I-4)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(1.00 g), triethylamine (0.58 g) and dichloromethane (5 ml) was addeddropwise for 5 minutes ethyl chlorothiocarbonate (0.56 g). The mixturewas stirred at room temperature for 1 hour. To the solution was addedwater (30 ml). The mixture was extracted with diethylether (60 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.74 g, yield: 56%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃)1.16 (6H, s), 1.21 (6H, d, J=6.9), 1.36 (3H, t,J=7.1), 2.63 (2H, s), 2.89 (2H, q, J=7.1), 3.15 (1H, q, J=6.9), 3.77(2H, s), 6.79–6.85 (1H,m), 7.12–7.16 (2H, m), 7.30–7.36 (1H, m).

Example 5 Preparation of2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(Compound I-5)

To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine(0.26 g), carbon dioxide (0.09 g) and N,N-dimethylformamide (2 ml) wasadded under ice-cooling 60% sodium hydride (0.05 g). The mixture wasstirred for 30 minutes. Methyliodide (0.17 g) was added thereto. Themixture was stirred at room temperature for 2 hours. To the solution wasadded water (30 ml), extracted with diethylether (60 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(0.14 g, yield: 40%) as a yellow crystal. M.p. 77–79° C.

¹H-NMR (δ ppm TMS/CDCl₃)1.20 (6H, d, J=6.9), 1.23 (6H, s), 2.65 (3H, s),2.68 (2H, s), 3.11 (1H, q, J=6.9), 4.51 (2H, s), 6.83–6.90 (1H, m),7.11–7.18 (2H, m), 7.28–7.35 (1H, m).

The following Reference Example 5 was carried out in accordance withReference Example 2 and 3.

Reference Example 5 Preparation of2-(2-isopropylphenyl)imino-1,3-thiazolidine (Compound 6)

To a solution of (2-isopropylphenyl)isothiocyanate (2.00 g) indiethylether (20 ml) was added 2-aminoethanol (0.69 g). The mixture wasstirred at room temperature for 1 hour and concentrated under reducedpressure. To the obtained oil was added concentrated hydrochloric acid(5 ml). The mixture was refluxed for 3 hours. The reaction mixture wascooled to room temperature and poured into an aqueous solution of 20%sodium hydroxide (25 ml). The mixture was extracted with dichloromethane(60 ml), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give2-(2-isopropylphenyl)imino-1,3-thiazolidine (1.80 g, yield: 73%) as awhite crystal. M.p. 76–77° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.20(6H, d, J=6.7), 3.15(1H, q, J=6.7),3.27(2H, t, J=6.7), 3.67(2H, t, J=6.7), 6.95–6.99(1H, m), 7.05–7.19(2H,m), 7.22–7.26(1H, m).

The following Example 6 and 7 were carried out by using2-(2-isopropylphenyl)imino-1,3-thiazolidine prepared in ReferenceExample 5.

Example 6 Preparation of3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-1,3-thiazolidine(Compound I-6)

To a mixture of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.25 g),triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for5 minutes ethyl chlorothiocarboxylate (0.15 g). The mixture was stirredfor 2 hours. To the solution was added water (30 ml). The mixture wasextracted with diethylether (60 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane/ethylacetate) to give3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.27g, yield: 77%) as a white crystal. M.p. 79–81° C.

¹H-NMR (δ ppm TMS/CDCl₃) 1.20 (6H, d, J=6.9), 1.30 (3H, t, J=7.4), 2.90(2H, t, J=7.4), 3.15 (2H, t, J=7.4), 3.20 (1H, q, J=6.9), 4.31 (2H, t,J=7.4), 6.79–6.82 (1H, m), 7.07–7.16 (2H, m), 7.28–7.32 (1H, m).

Example 7 Preparation of2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-1,3-thiazolidine(Compound I-7)

To a mixture of 2-(2-isopropylphenyl)imino-1,3-thiazolidine (0.22 g),carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was addedunder ice-cooling 60% sodium hydride (0.05 g). The mixture was stirredfor 30 minutes. Methyliodide (0.17 g) was added thereto. The mixture wasstirred at room temperature for 2 hours. To the mixture was added water(30 ml). The mixture was extracted with diethylether (60 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give2-(2-isopropylphenyl)imino-3-(methylthio)thiocarbonyl-1,3-thiazolidine(0.14 g, yield: 45%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.23 (6H, d, J=6.9), 2.65 (3H, s), 2.90 (2H, t,J=7.4), 3.20 (1H, q, J=6.9), 4.45 (2H, t, J=7.4), 6.79–6.82 (1H, m),7.07–7.16 (2H, m), 7.28–7.32 (1H, m).

Reference Example 6 Preparation of (2-methoxybenzyl)isothiocyanate(Compound 8)

To a solution of 2-methoxybenzylamine (1.80 g) in diethylether (20 ml)was added dropwise under ice-cooling for 10 minutes thiophosgene (1.54g). The mixture was stirred at room temperature for 1 hour. To thereaction solution was added water (30 ml), extracted with diethylether(60 ml), dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give (2-methoxybenzyl)isothiocyanate (2.35 g, yield:99%) as brown oil.

¹H-NMR (δ ppm TMS/CDCl₃) 3.86(3H, s), 4.70(2H, s), 6.88 (1H, d, J=7.4),6.98(1H, t, J=7.4), 7.24–7.30(2H, m).

Reference Example 7 Preparation ofN-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (Compound9)

To a solution of (2-methoxybenzyl)isothiocyanate (2.35 g) indiethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.34 g).The mixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane/ethyl acetate) to giveN-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (3.70 g,yield: 99%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 3.25(2H, s), 3.55(2H, d, J=6.3),3.86(3H, s), 4.70(2H, s), 6.50(1H, brs), 6.88(1H, d, J=7.4), 6.95(1H, t,J=7.4), 7.24–7.30(2H, m).

Reference Example 8 Preparation of2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (Compound 10)

To a mixture ofN-(2-methoxybenzyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (3.70 g),triphenylphosphine (3.44 g) and tetrahydrofuran (20 ml) was addeddropwise for 10 minutes diethyl azodicarboxylate (2.28 g). The mixturewas stirred at room temperature for 2 hours. To the solution was addedwater (40 ml). The mixture was extracted with dichloromethane (90 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.87 g, yield: 25%)as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.05(6H, s,), 2.75(2H, s), 3.23(2H, s),3.83(3H, s), 4.41(2H, s), 6.86–6.95(1H, m), 7.20–7.30(1H, m), 7.44–7.48(2H, m).

The following Examples 8 and 9 were carried out by using2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine prepared in ReferenceExample 8.

Example 8 Preparation of3-(ethylthiocarbonyl)-2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine(Compound I-8)

To a mixture of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine (0.28g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwisefor 5 minutes ethyl chlorothiocarboxylate (0.17 g). The mixture wasstirred at room temperature for 1 hour. To the reaction solution wasadded water (30 ml), extracted with diethylether (60 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give3-(ethylthiocarbonyl)-2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine(0.20 g, yield: 57%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.15 (6H, s), 1.25 (3H, t, J=7.4), 2.69 (2H,s), 2.83 (2H, q, J=7.4), 3.69 (2H, s), 3.84 (3H, s), 4.61 (2H, s), 6.86(1H, d, J=8.2), 6.96 (1H, t, J=8.2), 7.26 (1H, t, J=8.2), 7.55 (1H, t,J=8.2).

Example 9 Preparation of2-(2-methoxybenzyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(Compound I-9)

To a mixture of 2-(2-methoxybenzyl)imino-5,5-dimethyl-1,3-thiazine(0.27g), carbon disulfide (0.09 g) and N,N-dimethylformamide (2 ml) was addedunder ice-cooling 60% sodium hydride (0.05 g). The mixture was stirredfor 30 minutes. Methyl iodide (0.17 g) was added thereto. The mixturewas stirred at room temperature for 2 hours. To the solution was addedwater (30 ml). The mixture was extracted with diethylether (60 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give2-(2-methoxybenzyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(0.20 g, yield: 57%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.25 (6H, s), 2.56 (3H, s), 2.72 (2H, s), 3.85(3H, s), 4.43 (2H, s), 4.63 (2H, s), 6.86–6.88(2H, m), 7.20–7.30 (1H,m), 7.44–7.48 (1H, m).

Reference Example 9 Preparation of (2-methoxyphenethyl)isothiocyanate(Compound 12)

To a solution of 2-methoxyphenethylamine (1.98 g) in diethylether (20ml) was added dropwise under ice-cooling thiophosgene (1.54 g). Themixture was stirred at room temperature for 1 hour. To the solution wasadded water (30 ml). The mixture was extracted with diethylether (60ml), dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give (2-methoxyphenethyl)isothiocyanate (1.80 g,yield: 71%) as brown oil.

¹H-NMR (δ ppm TMS/CDCl₃) 3.00(2H, t, J=7.4), 3.70(2H, t, J=7.4),3.86(3H, s), 6.88–6.95(2H, m), 7.15(1H, d, J=7.4), 7.24(1H, t, J=7.4).

Reference Example 10 Preparation ofN-(2-methoxyphenethyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea(Compound 13)

To a solution of (2-methoxyphenethyl)isothiocyanate (2.35 g) indiethylether (20 ml) was added 3-amino-2,2-dimethylpropanol (1.34 g).The mixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane/ethyl acetate) to giveN-(2-methoxyphenethyl)-N′-(1-hydroxy-2′,2-dimethyl)propylthiourea (2.45g, yield 89%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 0.82(6H, s), 2.90(2H, t, J=7.4), 3.25(2H, s),3.55(2H, d, J=6.3), 3.70(2H, t, J=7.4), 3.86(3H, s), 6.50(1H, brs),6.88–6.95(2H, m), 7.15(1H, m), 7.24(1H, m).

Reference Example 11 Preparation of2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (Compound 14)

To a mixture ofN-(2-methoxyphenethyl)-N′-(1-hydroxy-2,2-dimethyl)propylthiourea (2.40g), triphenylphosphine (2.12 g) and tetrahydrofuran (20 ml) was addeddropwise for 10 minutes diethyl azodicarboxylate (2.28 g). The mixturewas stirred at room temperature for 2 hours. To the solution was addedwater (40 ml). The mixture was extracted with dichloromethane (90 ml),dried over magnesium sulfate and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine (0.70 g, yield:31%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.05(6H, s,), 2.72(2H, s), 2.80(2H, t, J=7.4),3.25(2H, s), 3.55(2H, d, J=6.3), 3.83(3H, s), 6.83–6.95(2H, m), 7.15(1H,m), 7.24(1H, m).

The following Examples 10 and 11 were carried out by using2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine prepared inExample 11.

Example 10 Preparation of3-(ethylthiocarbonyl)-2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine(Compound I-10)

To a mixture of 2-(2-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine(0.28 g), triethylamine (0.15 g) and dichloromethane (5 ml) was addeddropwise for 3 minutes ethyl chlorothiocarbonate (0.15 g). The mixturewas stirred at room temperature for 2 hours. To the solution was addedwater (30 ml). The mixture was extracted with diethylether (60 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give2-(2-methoxyphenethyl)imino-N-(ethylthiocarbamoyl)-5,5-dimethyl-1,3-thiazine(0.21 g, yield: 60%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.11 (6H, s), 1.26 (3H, t, J=7.4), 2.61 (2H,s), 2.83 (2H, q, J=7.4), 2.99–3.05 (2H, m), 3.61–3.66 (2H, m), 3.62 (2H,s), 3.82 (3H, s), 6.86–6.91 2H, m), 7.17–7.26 (2H, m).

Example 11 Preparation of2-(2-methoxyphenethyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(Compound I-11)

To a mixture of 1-(1-methoxyphenethyl)imino-5,5-dimethyl-1,3-thiazine(0.28 g), carbondisulfide (0.09 g) and N,N-dimethylformamide (2 ml) wasadded under ice-cooling 60% sodium hydride (0.05 g). The mixture wasstirred for 30 minutes. Methyliodide (0.17 g) was added thereto. Themixture was stirred at room temperature for 2 hours. To the solution wasadded water (30 ml). The mixture was extracted with diethylether (60ml), dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The obtained residue was chromatographed(n-hexane/ethyl acetate) to give2-(2-methoxyphenethyl)imino-3-(methylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine(0.18 g, yield: 50%) as colorless oil.

¹H-NMR (δ ppm TMS/CDCl₃) 1.19 (6H, s), 2.55 (3H, s), 2.64 (2H, s), 3.05(2H, t, J=7.5), 3.66 (2H, t, J=7.5), 3.84 (3H, s), 4.35 (2H, s),6.84–6.91 (2H, m), 7.17–7.30 (2H, m).

The compounds shown in the following tables were prepared in accordancewith the above Example. The numbers of left column in Tables representCompound No.

TABLE 1

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-16 H H H H H COSEt Me Me I-17 F H H H H COSEtMe Me I-18 Cl H H H H COSEt Me Me I-19 Me H H H H COSEt Me Me I-20 Et HH H H COSEt Me Me I-21 Pr H H H H COSEt Me Me I-22 Bu H H H H COSEt MeMe I-23 Bu^(s) H H H H COSEt Me Me I-24 Bu^(t) H H H H COSEt Me Me I-25Ph H H H H COSEt Me Me I-26 CF₃ H H H H COSEt Me Me I-27 OMe H H H HCOSEt Me Me I-28 OEt H H H H COSEt Me Me I-29 OPr^(i) H H H H COSEt MeMe I-30 SMe H H H H COSEt Me Me I-31 SEt H H H H COSEt Me Me I-32SPr^(i) H H H H COSEt Me Me I-33 NMe₂ H H H H COSEt Me Me I-34 H Pr^(i)H H H COSEt Me Me I-35 H H Cl H H COSEt Me Me I-36 H H Pr^(i) H H COSEtMe Me I-37 H H NO₂ H H COSEt Me Me I-38 Me Me H H H COSEt Me Me I-39 MeH Me H H COSEt Me Me I-40 Me H H Me H COSEt Me Me I-41 Me H H H Me COSEtMe Me I-42 H Me Me H H COSEt Me Me I-43 H Me H Me H COSEt Me Me I-44 MeH Cl H H COSEt Me Me

TABLE 2

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-45 Cl H Me H H COSEt Me Me I-46 Pr^(i) H NO₂ HH COSEt Me Me I-47 Pr^(i) H H H NO₂ COSEt Me Me I-48 NO₂ H NO₂ H H COSEtMe Me I-49 Pr H H H H COSMe Me Me I-50 Pr^(i) H H H H COSMe Me Me I-51Bu^(s) H H H H COSMe Me Me I-52 H Pr^(i) H H H COSMe Me Me I-53 H OMeOMe H H COSMe Me Me I-54 H —OCH₂O— H H COSMe Me Me I-55 H OMe OMe OMe HCOSMe Me Me I-56 Et H H H H CSSMe Me Me I-57 Bu^(s) H H H H CSSMe Me MeI-58 CH₂OMe H H H H CSSMe Me Me I-59 CH(Me)OMe H H H H CSSMe Me Me I-60OMe H H H H CSSMe Me Me I-61 OEt H H H H CSSMe Me Me I-62 SMe H H H HCSSMe Me Me I-63 SEt H H H H CSSMe Me Me I-64 SPr^(i) H H H H CSSMe MeMe I-65 SOMe H H H H CSSMe Me Me I-66 SO₂Me H H H H CSSMe Me Me I-67SOEt H H H H CSSMe Me Me I-68 NMe₂ H H H H CSSMe Me Me I-69 H Pr^(i) H HH CSSMe Me Me I-70 H H Cl H H CSSMe Me Me

TABLE 3

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-71 Me H Me H H CSSMe Me Me I-72 Me H H Me HCSSMe Me Me I-73 Me H H H Me CSSMe Me Me I-74 H Me Me H H CSSMe Me MeI-75 H Me H Me H CSSMe Me Me I-76 OMe OMe H H H CSSMe Me Me I-77 H OMeOMe H H CSSMe Me Me I-78 OMe H H OMe H CSSMe Me Me I-79 OMe H OMe HCSSMe Me Me I-80 H —OCH₂O— H H CSSMe Me Me I-81 Pr^(i) H NO₂ H H CSSMeMe Me I-82 Pr^(i) H H H NO₂ CSSMe Me Me I-83 H OMe OMe OMe H CSSMe Me MeI-84 Pr^(i) H H H H CSSEt Me Me I-85 Bu^(s) H H H H CSSEt Me Me I-86 OEtH H H H CSSEt Me Me I-87 SMe H H H H CSSEt Me Me I-88 H Pr^(i) H H HCSSEt Me Me  I-118 H OEt OEt H H CSSMe Me Me  I-119 OMe H Me H H CSSMeMe Me  I-120 OMe H H Me H CSSMe Me Me  I-121 H OMe Me H H CSSMe Me Me I-122 Me Me H H H CSSMe Me Me  I-123 N(Me)Ac H H H H CSSMe Me Me

TABLE 4

R⁶ R⁷ R⁸ I-89 COPr Me Me I-90 COOMe Me Me I-91 COOPr Me Me I-92 CONHEtMe Me I-93 COCH₂OMe Me Me I-94 COCH₂SMe Me Me I-95 COCH₂SEt Me Me I-96CSOEt Me Me I-97 CSNHEt Me Me I-98 CSSPr Me Me I-99 CSSPr^(i) Me Me I-100 CSSBn Me Me

TABLE 5

R¹ R² R³ n R⁶ R⁷ R⁸ 1-101 H H Cl 1 COSEt Me Me 1-102 H H Cl 1 CSSMe MeMe 1-103 Cl H Cl 2 COSEt Me Me 1-104 Cl H Cl 2 CSSMe Me Me

TABLE 6

R⁶ W I-105 COSEt

I-106 COSEt

I-107 COSEt

I-108 COSEt

I-109 COSEt

I-110 COSEt

I-111 COSEt

I-112 COSEt

I-113 CSSMe

I-114 CSSMe

I-115 CSSMe

I-116 CSSMe

I-117 CSSMe

TABLE 7

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-124 H H OEt H H CSSMe Me Me I-125 H OEt H H HCSSMe Me Me I-126 H H OMe H H CSSMe Me Me I-127 H OMe H H H CSSMe Me MeI-128 H OEt OMe H H CSSMe Me Me I-129 H OPr OMe H H CSSMe Me Me I-130 HOEt OEt H H CSSMe Me Me I-131 H H OPr H H CSSMe Me Me I-132 H OPr H H HCSSMe Me Me I-133 H H OBu H H CSSMe Me Me I-134 H OBu H H H CSSMe Me MeI-135 H OMe OEt H H CSSMe Me Me I-136 H OMe OPr H H CSSMe Me Me I-137 HOBu OMe H H CSSMe Me Me I-138 H H OPr^(i) H H CSSMe Me Me I-139 HOPr^(i) H H H CSSMe Me Me I-140 H H H H H CSSMe Me Me I-141 F H H H HCSSMe Me Me I-142 Cl H H H H CSSMe Me Me I-143 H Cl H H H CSSMe Me MeI-144 Me H H H H CSSMe Me Me I-145 H Me H H H CSSMe Me Me I-146 H H Me HH CSSMe Me Me I-147 H Bu H H H CSSMe Me Me I-148 H H Bu H H CSSMe Me Me

TABLE 8

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-149 Bu^(t) H H H H CSSMe Me Me I-150 H H Et HH CSSMe Me Me I-151 H Et H H H CSSMe Me Me I-152 H H F H H CSSMe Me MeI-153 H F H H H CSSMe Me Me I-154 H H Pr^(i) H H CSSMe Me Me I-155 H HMorpholino H H CSSMe Me Me I-156 H Ac H H H CSSMe Me Me I-157 H H Br H HCSSMe Me Me I-158 H Br H H H CSSMe Me Me I-159 Br H H H H CSSMe Me MeI-160 H C(Me)═NOMe H H H CSSMe Me Me I-161 H H Ac H H CSSMe Me Me I-162H H C(Me)═NOMe H H CSSMe Me Me I-163 OPr^(i) H H H H CSSMe Me Me I-164Pr H H H H CSSMe Me Me I-165 CF₃ H H H H CSSMe Me Me I-166 H H OPh H HCSSMe Me Me I-167 H H Pr H H CSSMe Me Me I-168 H H Bu^(t) H H CSSMe MeMe I-169 H CF₃ H H H CSSMe Me Me I-170 H H CF₃ H H CSSMe Me Me I-171Pr^(i) H NHAc H H CSSMe Me Me I-172 Pr^(i) H H H NHAc CSSMe Me Me I-173H COOMe H H OMe CSSMe Me Me

TABLE 9

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-174 Morpholino H H H H CSSMe Me Me I-175 HMorpholino H H H CSSMe Me Me I-176 Pr^(i) H H COOEt H CSSMe Me Me I-177H H Piperidino H H CSSMe Me Me I-178 Pyrrolidino H H H H CSSMe Me MeI-179 H SMe H H H CSSMe Me Me I-180 H H SMe H H CSSMe Me Me I-181 OCF₃ HH H H CSSMe Me Me I-182 H OCF₃ H H H CSSMe Me Me I-183 H H OCF₃ H HCSSMe Me Me I-184 H H 3-Pyridyl H H CSSMe Me Me I-185 H 3-Pyridyl H H HCSSMe Me Me I-186 3-Pyridyl H H H H CSSMe Me Me I-187 OPh H H H H CSSMeMe Me I-188 H OEt OEt H H COOMe Me Me I-189 OMe H H H H COOMe Me MeI-190 H H Et H H COOMe Me Me I-191 H H Pr^(i) H H COOMe Me Me I-192 OMeH H H H COSMe Me Me I-193 H H Et H H COSMe Me Me I-194 H H Pr^(i) H HCOSMe Me Me I-195 H H OEt H H COSMe Me Me I-196 H OMe OEt H H COSMe MeMe I-197 H Piperidino H H H CSSMe Me Me I-198 H H NEt₂ H H CSSMe Me Me

TABLE 10

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-199 OMe H COOMe H H CSSMe Me Me I-200 H2-Oxopyr- H H H CSSMe Me Me rolidino I-201 H OPh H H H CSSMe Me Me I-202H H Ph H H CSSMe Me Me I-203 Ph H H H H CSSMe Me Me I-204 H Ph H H HCSSMe Me Me I-205 Pr^(i) H H H H CSOMe Me Me I-206 Pr^(i) H l H H CSSMeMe Me I-207 OMe H (Morpho- H H CSSMe Me Me lino)CO I-208 H H NMe₂ H HCSSMe Me Me I-209 H NMe₂ H H H CSSMe Me Me I-210 N(Me)Et H H H H CSSMeMe Me I-211 N(Me)Pr H H H H CSSMe Me Me I-212 NEt₂ H H H H CSSMe Me MeI-213 F H H H F CSSMe Me Me I-214 Pr^(i) H Cl H H CSSMe Me Me I-215 NMe₂Me H H H CSSMe Me Me I-216 NMe₂ H Me H H CSSMe Me Me I-217 NMe₂ H H Me HCSSMe Me Me I-218 NMe₂ H H Cl H CSSMe Me Me I-219 Me H H H Me CSSMe MeMe I-220 NMe₂ H H H H CSSEt Me Me I-221 H NMe₂ H H H CSSEt Me Me I-222NMe₂ H Me H H CSSEt Me Me I-223 H H Pr^(i) H H CSSEt Me Me

TABLE 11

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-224 OMe H CONHMe H H CSSMe Me Me I-225 OCHF₂ HH H H CSSMe Me Me I-226 H OCHF₂ H H H CSSMe Me Me I-227 H NEt₂ H H HCSSMe Me Me I-228 NMe₂ H Cl H H CSSMe Me Me I-229 NMe₂ H F H H CSSMe MeMe I-230 NMe₂ H H F H CSSMe Me Me I-231 NMe₂ H Et H H CSSMe Me Me I-232NMe₂ H H Et H CSSMe Me Me I-233 NMe₂ H Cl H H CSSEt Me Me I-234 NMe₂ H FH H CSSEt Me Me I-235 NMe₂ H Et H H CSSEt Me Me I-236 Pr^(i) H H H HCSSBu^(s) Me Me I-237 Pr^(i) H H H H CSSBu^(i) Me Me I-238 Pr^(i) H H HH CSNHMe Me Me I-239 Me NMe₂ H H H CSSMe Me Me I-240 NMe₂ OMe H H HCSSMe Me Me I-241 H NMe₂ Me H H CSSMe Me Me I-242 NMe₂ Cl H H H CSSMe MeMe I-243 H NMe₂ OMe H H CSSMe Me Me I-244 Pr^(i) H H H H CSSEt Et EtI-245 Pr^(i) H H H H Me Me Me I-246 Pr^(i) H H H H Pr Me Me I-247 Pr^(i)H H H H Pr^(i) Me Me I-248 Pr^(i) H H H H Bu^(i) Me Me

TABLE 12

A R⁶ R⁷ R⁸ I-249

CSSMe Me Me I-250

CSSMe Me Me I-251

CSSMe Me Me I-252

CSSMe Me Me I-253

CSSMe Me Me I-254

CSSMe Me Me I-255

CSSMe Me Me I-256

CSSMe Me Me I-257

CSSMe Me Me I-258

CSSMe Me Me I-259

CSSMe Me Me I-260

CSSMe Me Me I-261

CSSMe Me Me

TABLE 13

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-262 NMe₂ H OMe H H CSSMe Me Me I-263 NMe₂ H HOMe H CSSMe Me Me I-264 Me NEt₂ H H H CSSMe Me Me I-265 H NEt₂ Me H HCSSMe Me Me I-266 H NEt₂ OMe H H CSSMe Me Me I-267 Bu^(s) H H H H CSSMeEt Et I-268 Pr^(i) H H H H CSSMe Pr Pr I-269 Pr^(i) H H H H CSSMe—(CH₂)₄— I-270 Pr^(i) H H H H CSSMe —(CH₂)₅—

TABLE 14

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ I-271 Pr^(i) H H H H SO₂Me Me Me I-272 Pr^(i) HH H H

Me Me I-273 Pr^(i) H H H H

Me Me I-274 H Pr^(i) H H H

Me Me I-275 H Pr^(i) H H H SO₂Et Me Me I-276 H Pr^(i) H H H

Me Me I-277 H Pr^(i) H H H

Me Me I-278 H Pr^(i) H H H

Me Me I-279 H Pr^(i) H H H

Me Me I-280 H Pr^(i) H H H

Me Me

Physical Date (M.p., ¹H-NMR) of the compounds in the above Tables areshown in the following Tables.

TABLE 15 Comp. No. Physical Date No M.p. I-16 57–59° C. 1.16(6H, s),1.31(3H, t, J=7.3), 2.64(2H, s), 2.91(2H, q, J=7.3), 3.78(2H, s),6.96(1H, dd, J=7.4, 1.2), 7.14(1H, t, J=7.4), 7.36(2H, t, J=7.4). I-171.15(6H, s), 1.31(3H, t, J=7.3), 2.67(2H, s), 2.91(2H, q J=7.3),3.77(2H, s), 7.10–7.15(4H, m). I-18 1.16(6H, s), 1.31(3H, t, J=7.3),2.68(2H, s), 2.92(2H, q, J=7.3), 3.80(2H, s), 6.96(1H, dd, J=7.7, 1.2),7.08(1H, dt, J=7.7, 1.6), 7.25(2H, t, J=7.4), 7.40(1H, d, J=7.4). I-191.15(6H, s), 1.27(3H, t, J=7.3), 2.24(3H, s), 2.62(2H, s), 2.92(2H, q,J=7.4), 3.77(2H, s), 6.83(1H, d, J=7.7), 7.04(1H, t, J=7.7),7.16–7.22(2H, m). I-20 1.15(6H, s), 1.19(3H, t, J=7.4), 1.31(3H, t,J=7.3), 2.62(2H, q, J=7.3), 2.65(2H, s), 2.94(2H, q, J=7.4), 3.77(2H,s), 6.83(1H, d, J=7.6), 7.10–7.22(3H, m). I-21 0.95(3H, t, J=7.3),1.15(6H, s), 1.30(3H, t, J=7.4), 1.50–1.64(2H, m), 2.56(2H, q, J=7.3),2.59(2H, s), 2.90(2H, q, J=7.4), 3.76(2H, s), 6.82(1H, d, J=7.3),7.06–7.28(3H, m). I-22 0.90(3H, t, J=7.1), 1.15(6H, s), 1.29(3H, t,J=7.4), 1.30–1.34(2H, m), 1.52–1.58(2H, m), 2.54(2H, q, J=7.1), 2.62(2H,s), 2.92(2H, q, J=7.4), 3.76(2H, s), 6.79(1H, dd, J=7.9, 1.4),7.06–7.28(3H, m). I-23 0.86(3H, t, J=7.4), 1.14(6H, s), 1.16(6H, d,J=6.9), 1.29(3H, t, J=7.4), 1.48–1.58(2H, m), 2.61(2H, s), 2.89(2H, q,J=7.4), 2.88–2.92(1H, m), 3.76(2H, d, J=13.6), 3.82(1H, d, J=13.6),6.82–6.88(1H, m), 7.10–7.18(1H, m), 7.23–7.29(1H, m). I-24 1.15(6H, s),1.27(3H, t, J=7.4), 1.33(9H, s), 2.68(2H, s), 2.86(2H, q, J=7.4),3.75(2H, s), 6.86(1H, dd, J=7.4, 1.6), 7.08–7.19(2H, m), 7.38(2H, dd,J=7.4, 1.6). I-25 0.99(6H, s), 1.25(3H, t, J=7.4), 2.45(2H, s), 2.82(2H,q, J=7.4), 3.51(2H, s), 6.98(1H, d, J=7.7), 7.20–7.36(6H, m), 7.43(2H,m). I-26 82–83° C. 1.15(6H, s), 1.29(3H, t, J=7.3), 2.66(2H, s),2.89(2H, q, J=7.4), 3.77(2H, s), 6.98(1H, d, J=7.6), 7.19(1H, t, J=7.6),7.49(1H, t, J=7.6), 7.64(1H, d, J=7.6).

TABLE 16 Comp. No. Physical Date No M.p. I-27 1.16(6H, s), 1.25(3H, t,J=7.4), 2.62(2H, s), 2.88(2H, q, J=7.4), 3.78(2H, s), 3.83(3H, s),6.91–6.96(3H, m), 7.05–7.14(1H, m). I-28 1.15(6H, s), 1.30(3H, t,J=7.4), 1.40(3H, t, J=7.0), 2.60(2H, s), 2.90(2H, q, J=7.4), 3.78(2H,s), 4.08(2H, q, J=7.0), 6.90–6.94(3H, m), 7.06–7.08(1H, m). I-291.14(6H, s), 1.29(6H, d, J=7.4), 1.31(6H, d, J=6.0), 2.59(2H, s),2.89(2H, q, J=7.4), 3.76(2H, s), 4.50(1H, q, J=6.0), 6.90–6.93(3H, m),7.01–7.07(1H, m). I-30 78–80° C. 1.15(6H, s), 1.29(3H, t, J=7.4),2.43(3H, s), 2.63(2H, s), 2.89(2H, q, J=7.4), 3.78(2H, s), 6.87–6.91(1H,m), 7.05–7.14(2H, m), 7.20–7.29(1H, m). I-31 55–57° C. 1.15(6H, s),1.29(3H, t, J=7.4), 1.31(3H, t, J=7.4), 2.66(2H, s), 2.89(2H, q, J=7.4),2.94(2H, q, J=7.4), 3.78(2H, s), 6.91(1H, dd, J=7.4, 1.6), 7.08–7.20(2H,m), 7.32(1H, dd, J=7.4, 1.6). I-32 1.15(6H, s), 1.27(6H, d, J=6.6),1.28(6H, d, J=7.4), 2.65(2H, s), 2.88(2H, q, J=7.4), 3.38–3.42(1H, m),3.78(2H, s), 6.90(1H, dd, J=7.7, 1.6), 7.08–7.20(2H, m), 7.32(1H, dd,J=7.7, 1.6). I-33 1.15(6H, s), 1.29(3H, t, J=7.4), 2.60(2H, s), 2.71(6H,s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.90–6.98(3H, m), 7.05–7.10(1H, m).I-34 1.16(6H, s), 1.27(6H, d, J=6.9), 1.31(3H, t, J=7.4), 2.64(2H, s),2.91(2H, q, J=7.4), 2.98(1H, q, J=6.9), 3.77(2H, s), 6.78–6.83(2H, m),7.01–7.04(1H, m), 7.25–7.27(1H, m). I-35 68–69° C. 1.16(6H, s), 1.30(3H,t, J=7.3), 2.66(2H, s), 2.90(2H, q, J=7.3), 3.76(2H, s) 6.98(2H, dd,J=6.6, 2.1), 7.31(2H, dd, J=6.6, 2.1). I-36 67–69° C. 1.15(6H, s),1.20(6H, d, J=6.9), 1.26(3H, t, J=7.4), 2.64(2H, s), 2.86(2H, q, J=7.4),2.89(1H, q, J=6.9), 3.75(2H, s), 6.98(2H, d, J=8.2), 7.20(2H, d, J=8.3).I-37 125–126° C. 1.15(6H, s), 1.30(3H, t, J=7.3), 2.72(2H, s), 2.92(2H,q, J=7.3), 3.78(2H, s), 7.05(2H, d, J=8.3), 7.31(2H, d, J=8.3). I-3876–78° C. 1.15(6H, s), 1.30(3H, t, J=7.4), 2.14(3H, s), 2.29(3H, s),2.63(2H, s), 2.89(2H, q, J=7.4), 3.77(2H, s), 6.70(1H, d, J=7.9),6.94(1H, d, J=7.9), 7.06(1H, s).

TABLE 17 Comp. No. Physical Date No M.p. I-39 1.14(6H, s), 1.29(3H, t,J=7.4), 2.21(3H, s), 2.32(3H, s), 2.65(2H, s), 2.89(2H, q, J=7.4),3.76(2H, s), 6.73(1H, d, J=7.9), 6.97(1H, d, J=7.9), 7.02(1H, s). I-401.15(6H, s), 1.30(3H, t, J=7.4), 2.19(3H, s), 2.31(3H, s), 2.64(2H, s),2.89(2H, q, J=7.4), 3.77(2H, s), 6.65(1H, s), 6.86(1H, d, J=7.9),7.07(1H, d, J=7.7). I-41 59–61° C. 1.15(6H, s), 1.30(3H, t, J=7.3),2.19(6H, s), 2.62(2H, s), 2.90(2H, q, J=7.3), 3.78(2H, s), 6.90–6.96(1H,m), 7.02–7.08(2H, m). I-42 1.15(6H, s), 1.31(3H, t, J=7.4), 2.26(3H, s),2.28(3H, s), 2.65(2H, s), 2.91(2H, q, J=7.4), 3.78(2H, s), 6.74(1H, dd,J=7.9, 1.8), 6.80(1H, d, J=1.8), 7.13(1H, d, J=7.7). I-43 1.15(6H, s),1.31(3H, t, J=7.4), 2.31(6H, s), 2.63(2H, s), 2.90(2H, q, J=7.4),3.76(2H, s), 6.58(2H, s), 6.77(1H, s). I-44 1.15(6H, s), 1.28(3H, t,J=7.4), 2.21(3H, s), 2.64(2H, s), 2.90(2H, q, J=7.4), 3.76(2H, s),6.74(1H, d, J=8.2), 7.10–7.18(2H, m). I-45 1.15(6H, s), 1.28(3H, t,J=7.4), 2.31(3H, s), 2.66(2H, s), 2.92(2H, q, J=7.4), 3.78(2H, s),6.74(1H, d, J=7.8), 7.04(1H, d, J=7.8), 7.25(1H, d, J=7.8). I-46119–120° C. 1.16(6H, s), 1.25(6H, d, J=6.9), 1.29(3H, t, J=7.4),2.69(2H, s), 2.90(2H, q, J=7.4), 3.15(1H, m), 3.79(2H, s), 6.92(1H, d,J=8.7), 8.01(1H, dd, J=8.5, 2.4), 8.18(1H, d, J=2.4). I-47 1.17(6H, s),1.23(6H, d, J=6.9), 1.30(3H, t, J=7.4), 2.69(2H, s), 2.91(2H, q, J=7.4),3.19(1H, m), 3.79(2H, s), 7.41(1H, d, J=8.7), 7.71(1H, d, J=2.4),7.92(1H, dd, J=8.7, 2.4). I-48 1.15(6H, s), 1.30(3H, t, J=7.4), 2.73(2H,s), 2.93(2H, q, J=7.4), 3.82(2H, s) 7.15(2H, d, J=8.3), 8.48(1H, dd,J=8.3, 1.4), 8.90(1H, d, J=8.3). I-49 64–66° C. 0.95(3H, t, J=7.3),1.15(6H, s), 1.50–1.64(2H, m), 2.32(3H, s), 2.56(2H, q, J=7.3), 2.63(2H,s), 3.78(2H, s), 6.82(1H, d, J=7.3), 7.06–7.28(3H, m). I-50 95–96° C.1.16(6H, s), 1.20(6H, d, J=6.9), 2.32(3H, s), 2.64(2H, s), 3.12(1H, q,J=6.9), 3.79(2H, s), 6.78–6.82(1H, m), 7.11–7.20(2H, m), 7.30–7.34(1H,m).

TABLE 18 Comp. No. Physical Date No M.p. I-51 53–56° C. 0.85(3H, t,J=7.3), 1.15(6H, d, J=6.9), 1.18(6H, s), 1.57–1.70(2H, m), 2.31(3H, s),2.62(2H, s), 2.91(1H, q, J=6.9), 3.74(1H, d, J=13.7), 3.78(1H, d,J=13.7), 6.78–6.83(1H, m), 7.11–7.18(2H, m), 7.23–7.30(1H, m). I-5288–90° C. 1.17(6H, s), 1.27(6H, d, J=6.9), 2.33(3H, s), 2.65(2H, s),2.91(1H, q, J=6.9), 3.79(2H, s), 6.78–6.83(2H, m), 7.01–7.04(1H, m),7.20–7.24(1H, m). I-53 1.16(6H, s), 2.32(3H, s), 2.65(2H, s), 3.77(2H,s), 3.87(6H, s), 6.51–6.59(2H, m), 6.80–6.89(1H, m). I-54 102–104° C.1.15(6H, s), 2.31(3H, s), 2.65(2H, s), 3.76(2H, s), 5.96(2H, s),6.42(1H, dd, J=8.1, 1.8), 6.53(1H, d, J=1.8), 6.78(1H, d, J=8.1). I-55129–131° C. 1.16(6H, s), 2.32(3H, s), 2.67(2H, s), 3.78(2H, s), 3.85(6H,s), 3.86(3H, s), 6.20(2H, s) I-56 107–109° C. 1.17(3H, t, J=7.6),1.22(6H, s), 2.58(2H, q, J=7.6), 2.64(3H, s), 2.66(2H, s), 4.51(2H, s),6.91(1H, dd, J=7.5, 1.3), 7.02–7.19(2H, m), 7.23–7.28(1H, m). I-570.85(3H, t, J=7.3), 1.18(6H, d, J=6.9), 1.23(6H, s), 1.57–1.70(2H, m),2.64(3H, s), 2.66(2H, s), 2.88(1H, q, J=6.9), 4.38(1H, d, J=13.7),4.60(1H, d, J=13.7), 6.83–6.90(1H, m), 7.11–7.18(2H, m), 7.28–7.35(1H,m). I-58 85–87° C. 1.22(6H, s), 2.62(3H, s), 2.63(2H, s), 3.35(3H, s),4.40(2H, s), 4.48(2H, s), 6.93–6.99(1H, m), 7.11–7.29(2H, m),7.40–7.49(1H, m). I-59 113–114° C. 1.22(3H, s), 1.24(3H, s), 1.37(3H, d,J=6.4), 2.63(3H, s), 2.65(2H, s), 3.24(3H, s), 4.35(1H, d, J=13.6),4.55(1H, q, J=6.4), 4.66(1H, d, J=13.6), 6.91(1H, d, J=7.4),7.19–7.40(2H, m), 7.51(1H, d, J=7.4). I-60 128–130° C. 1.22(6H, s),2.62(3H, s), 2.65(2H, s), 3.85(3H, s), 4.53(2H, s), 6.93–6.99(2H, m),7.02–7.15(2H, m). I-61 100–101° C. 1.26(6H, s), 1.43(3H, t, J=7.4),2.66(2H, s), 2.67(3H, s), 4.08(2H, q, J=7.0), 4.55(2H, s), 6.95–6.99(3H,m), 7.11–7.18(1H, m). I-62 137–139° C. 1.23(6H, s), 2.43(3H, s),2.64(3H, s), 2.67(2H, s), 4.53(2H, s), 6.87–6.92(1H, m), 7.11–7.20(2H,m), 7.23–7.29(1H, m).

TABLE 19 Comp. No. Physical Date No M.p. I-63 103–105° C. 1.15(6H, s),1.29(3H, t, J=7.4), 1.31(3H, t, J=7.4), 2.66(2H, s), 2.89(2H, q, J=7.4),2.94(2H, q, J=7.4), 3.78(2H, s), 6.91(1H, dd, J=7.4, 1.6), 7.08–7.20(2H,m), 7.32(1H, dd, J=7.4, 1.6). I-64 125–126° C. 1.24(6H, s), 1.28(6H, d,J=6.6), 2.63(3H, s), 2.66(2H, s), 3.38–3.42(1H, m), 4.53(2H, s),6.97(1H, dd, J=7.7, 1.6), 7.08–7.20(2H, m), 7.32(1H, dd, J=7.7, 1.6).I-65 1.22(6H, s), 2.63(3H, s), 2.65(2H, d, J=13.6), 2.75(3H, s),4.17(1H, d, J=13.6), 4.77(1H, d, J=13.6), 7.06(1H, dd, J=7.7, 1.7),7.19–7.40(2H, m), 7.97(1H, dd, J=7.7, 1.7). I-66 147–149° C. 1.23(6H,s), 2.63(3H, s), 2.71(2H, s), 3.13(3H, s), 4.52(2H, s), 7.11(1H, m,),7.11–7.20(2H, m), 7.23–7.29(1H, m). I-67 129–130° C. 1.22(6H, s),1.23(3H, t, J=6.9), 2.63(3H, s), 2.66(2H, s), 2.70–2.85(1H, m),2.90–3.15(1H, m), 4.25(1H, d, J=13.6), 4.70(1H, d, J=13.6), 7.06(1H, d,J=7.5), 7.30–7.45(2H, m), 7.90(1H, d, J=7.5). I-68 100–102° C. 1.23(6H,s), 2.62(3H, s), 2.65(2H, s), 2.71(6H, s), 4.50(2H, s), 6.93–6.99(3H,m), 7.02–7.15(1H, m). I-69 1.23(6H, s), 1.25(6H, d, J=6.9), 2.64(3H, s),2.66(2H, s), 2.92(1H, q, J=6.9), 4.52(2H, s), 6.84–6.86(2H, m),7.08–7.13(1H, m), 7.28–7.32(1H, m). I-70 116–118° C. 1.23(6H, s),2.64(3H, s), 2.68(2H, s), 4.51(2H, s), 6.97(2H, d, J=8.6), 7.35(2H, d,J=8.6). I-71 103–105° C. 1.22(6H, s), 2.19(3H, s), 2.30(3H, s), 2.63(3H,s), 2.65(2H, s), 4.50(2H, s), 6.79(1H, d, J=7.9), 6.98(1H, d, J=7.9),7.02(1H, s). I-72 100–101° C. 1.23(6H, s), 2.18(3H, s), 2.32(3H, s),2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.71(1H, s), 6.88(1H, d, J=7.9),7.08(1H, t, J=7.9). I-73 93–95° C. 1.22(6H, s), 2.12(3H, s), 2.30(3H,s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.76(1H, d, J=7.9), 6.98(1H,d, J=7.9), 7.08(1H, t, J=7.9). I-74 126–128° C. 1.23(6H, s), 2.25(3H,s), 2.27(3H, s), 2.64(3H, s), 2.65(2H, s), 4.51(2H, s), 6.76(1H, d,J=7.9), 6.82(1H, s), 713(1H, d, J=7.9). I-75 96–98° C. 1.23(6H, s),2.32(6H, s), 2.63(3H, s), 2.65(2H, s), 4.51(2H, s), 6.64(2H, s),6.80(1H, s). I-76 1.22(6H, s), 2.64(3H, s), 2.65(2H, s), 3.79(3H, s),3.88(3H, s), 4.52(2H, s), 6.60(1H, d, J=7.9), 6.73(1H, d, J=7.9),7.04(1H, d, J=7.9).

TABLE 20 Comp. No. Physical Date No M.p. I-77 1.24(6H, s), 2.63(3H, s),2.68(2H, s), 3.87(6H, s), 4.50(2H, s), 6.61–6.65(2H, m), 6.85–6.89(1H,m). I-78 1.22(6H, s), 2.62(3H, s), 2.66(2H, s), 3.81(6H, s), 4.52(2H,s), 6.48(1H, dd, J=8.5, 2.4), 6.51(1H, d, J=2.4), 6.92(1H, d, J=8.5).I-79 1.22(6H, s), 2.62(3H, s), 2.64(2H, s), 3.77(6H, s), 4.52(2H, s),6.56(1H, d, J=2.4), 6.68(1H, dd, J=8.5, 2.4), 686(1H, d, J=8.5). I-80108–110° C. 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 4.49(2H, s), 6.04(2H,s), 6.50(1H, dd, J=8.1, 1.8), 6.61(1H, d, J=1.8), 6.83(1H, d, J=8.1).I-81 1.23(6H, s), 1.25(6H, d, J=6.9), 2.65(3H, s), 2.71(2H, s), 3.11(1H,q, J=6.9), 4.51(2H, s), 7.02(1H, d, J=8.5), 8.04(1H, dd, J=8.5, 2.7),8.21(1H, d, J=2.7). I-82 1.21(6H, s), 1.24(6H, d, J=6.9), 2.63(3H, s),2.66(2H, s), 3.17(1H, q, J=6.9), 4.51(2H, s), 7.45(1H, d, J=8.5),7.80(1H, d, J=2.4), 7.99(1H, dd, J=8.5, 2.4). I-83 1.24(6H, s), 2.64(3H,s), 2.68(2H, s), 3.85(6H, s), 3.86(3H, s), 4.51(2H, s), 6.28(2H, s).I-84 68–70° C. 1.22(6H, d, J=6.9), 1.23(6H, s), 1.35(3H, t, J=7.4),2.65(2H, s), 3.11(1H, q, J=6.9), 3.25(2H, q, J=6.9), 4.48(2H, s),6.89–6.92(1H, m), 7.14–7.20(2H, m), 7.30–7.34(1H, m). I-85 0.85(3H, t,J=7.4), 1.18(6H, d, J=6.9), 1.23(6H, s), 1.35(3H, t, J=7.4),1.57–1.70(2H, m), 2.56(2H, s), 2.87(1H, q, J=6.9), 3.25(2H, q, J=7.4),4.35(1H, d, J=13.7), 4.60(1H, d, J=13.7), 6.89–6.92(1H, m),7.10–7.18(2H, m), 7.30–7.34(1H, m). I-86 96–97° C. 1.23(6H, s), 1.36(3H,t, J=7.0), 1.40(3H, t, J=7.0), 2.63(2H, s), 3.27(2H, q, J=7.4), 4.06(2H,q, J=7.0), 4.51(2H, s), 6.92–7.08(3H, m), 7.11–7.15(1H, m). I-87105–106° C. 1.22(6H, s), 1.35(3H, t, J=7.4), 2.43(3H, s), 2.66(2H, s),3.26(2H, q, J=7.4), 4.50(2H, s), 6.95–6.98(1H, m), 7.10–7.17(2H, m),7.24–7.29(1H, m).

TABLE 21 Comp. No. Physical Date No M.p. I-88 1.23(6H, s), 1.25(6H, d,J=6.9), 1.35(3H, t, J=7.4), 2.66(2H, s), 2.90(1H, q, J=6.9), 3.28(2H, q,J=7.4), 4.50(2H, s), 6.84–6.88(2H, m), 7.08–7.13(1H, m), 7.28–7.32(1H,m). I-89 0.98(3H, t, J=7.4), 1.12(6H, s), 1.22(6H, d, J=6.9),1.72–1.80(2H, m), 2.58(2H, s), 2.90(2H, t, J=7.4), 3.06(1H, q, J=6.9),3.71(2H, s), 6.71–6.76(1H, m), 7.11–7.20(2H, m), 7.30–7.34(1H, m). I-90 99–101° C. 1.14(6H, s), 1.21(6H, d, J=6.9), 2.58(2H, s), 3.14(1H, q,J=6.9), 3.64(2H, s), 3.86(3H, s), 6.73–6.78(1H, m), 7.11–7.18(2H, m),7.28–7.35(1H, m). I-91 1.00(3H, t, J=7.3), 1.14(6H, s), 1.20(6H, d,J=6.9), 1.74(2H, q, J=7.3), 2.58(2H, s), 3.16(1H, q, J=6.9), 3.65(2H,s), 4.23(2H, q, J=6.9), 6.73–6.80(1H, m), 7.12–7.18(2H, m),7.31–7.34(1H, m). I-92 52–53° C. 1.13(6H, s), 1.19(6H, d, J=6.9),1.20(3H, t, J=7.4), 2.60(2H, s), 2.98(1H, q, J=6.9), 3.38(2H, q, J=7.4),3.77(2H, s), 6.73–6.78(1H, m), 7.09–7.18(2H, m), 7.28–7.32(1H, m). I-9376–78° C. 1.14(6H, s), 1.22(6H, d, J=6.9), 2.62(2H, s), 2.96(1H, q,J=6.9), 3.48(3H, s), 3.75(2H, s), 4.64(2H, s), 6.73–6.78(1H, m),7.10–7.17(2H, m), 7.25–7.32(1H, m). I-94 61–62° C. 1.14(6H, s), 1.20(6H,d, J=6.9), 2.23(3H, s), 2.68(2H, s), 2.93(1H, q, J=6.9), 3.71(2H, s),3.94(2H, s), 6.82–6.86(1H, m), 7.10–7.18(2H, m), 7.30–7.36(1H, m). I-9550–52° C. 1.13(6H, s), 1.20(6H, d, J=6.9), 1.31(3H, t, J=7.3), 2.65(2H,J=7.3), 2.68(2H, s), 2.90(1H, q, J=6.9), 3.71(2H, s), 3.97(2H, s),6.82–6.86(1H, m), 7.12–7.19(2H, m), 7.30–7.36(1H, m). I-96 73–75° C.1.21(6H, s), 1.22(6H, d, J=6.9), 1.42(3H, t, J=6.9), 2.61(2H, s),3.10(1H, q, J=6.9), 4.15(2H, s), 4.65(2H, q, J=6.9), 6.74–6.78(1H, m),7.14–7.20(2H, m), 7.30–7.34(1H, m). I-97 160–162° C. 1.18(6H, s),1.22(6H, d, J=6.9), 1.25(3H, t, J=7.4), 2.60(2H, s), 2.90(1H, q, J=6.9),3.71(2H, q, J=7.4), 4.40(2H, s), 6.74–6.78(1H, m), 7.14–7.20(2H, m),7.30–7.34(1H, m). I-98 1.04(3H, t, J=7.4), 1.20(6H, d, J=6.9), 1.27(6H,s), 1.73(2H, m), 2.64(2H, s), 3.12(1H, q, J=6.9), 3.22(2H, t, J=7.4),4.48(2H, s), 6.89–6.92(1H, m), 7.10–7.20(2H, m), 7.28–7.35(1H, m).

TABLE 22 Comp. No. Physical Date No M.p. I-99 113–114° C. 1.04(6H, d,J=6.9), 1.27(6H, s), 1.42(3H, d, J=6.9), 2.63(2H, s), 3.14(1H, q,J=6.9), 4.02(1H, q, J=6.9), 4.46(2H, s), 6.89–6.93(1H, m), 7.10–7.20(2H,m), 7.28–7.35(1H, m). I-100 1.10(6H, d, J=6.9), 1.22(6H, s), 2.64(2H,s), 3.08(1H, q, J=6.9), 4.48(2H, s), 4.49(2H, s), 6.83–6.90(1H, m),7.11–7.18(2H, m), 7.20–7.38(6H, m). I-101 1.15(6H, s), 1.25(3H, t,J=7.4), 2.70(2H, s), 2.87(2H, q, J=7.4), 3.69(2H, s), 4.55(2H, s),7.30–7.40(4H, m). I-102 1.24(6H, s), 2.57(3H, s), 2.73(2H, s), 4.43(2H,s), 4.58(2H, s), 7.23–7.40(4H, m). I-103 1.11(6H, s), 1.26(3H, t,J=7.4), 2.61(2H, s), 2.83(2H, q, J=7.4), 3.10(2H, t, J=7.4), 3.65(2H,s), 3.66(2H, t, J=7.4), 7.17(1H, dd, J=8.2, 2.1), 7.30(1H, t, J=8.2),7.36(1H, d, J=2.1). I-104 1.16(6H, s), 2.55(3H, s), 2.63(2H, s),3.13(2H, t, J=7.5), 3.69(2H, t, J=7.5), 4.35(2H, s), 7.15(1H, dd, J=8.2,2.1), 7.25(1H, t, J=8.2), 7.36(1H, d, J=2.1). I-105 1.20(6H, d, J=6.9),1.30(3H, t, J=7.4), 2.10–2.22(2H, m), 2.88(2H, t, J=6.4), 2.94(2H, q,J=7.4), 3.11(1H, q, J=6.9), 4.05(2H, t, J=7.4), 6.82–6.86(1H, m),7.10–7.16(2H, m), 7.28–7.34(1H, m). I-106 1.17–1.30(12H, m),1.45–1.52(1H, m), 1.90–1.96(1H, m), 2.92(2H, q, J=7.4), 2.95–3.05(2H,m), 3.14–3.23(1H, m), 3.72–3.75(1H, m), 7.20–7.30(2H, m), 7.40–7.45(2H,m). I-107 1.22(6H, d, J=6.9), 1.28(3H, d, J=6.6), 1.29(3H, t, J=7.4),1.75–1.77(1H, m), 2.29–2.34(1H, m), 2.88(2H, q, J=7.4), 3.14(1H, m),3.31–3.36(1H, m), 4.01–4.10(2H, m), 6.81–6.85(1H, m), 7.10–7.20(2H, m),7.28–7.35(1H, m). I-108 1.12(3H, d, J=6.6), 1.20(6H, d, J=6.9), 1.29(3H,t, J=7.4), 2.40–2.50(1H, m), 2.57(1H, dd, J=13.5, 6.6), 2.91(2H, q,J=7.4), 2.95(1H, m), 3.14(1H, m), 3.45(1H, dd, J=13.5, 8.4), 4.30(1H,dd, J=13.5, 8.4), 6.81–6.85(1H, m), 7.10–7.20(2H, m), 7.28–7.35(1H, m).

TABLE 23 Comp. No. Physical Date No M.p. I-109 0.88(6H, t, J=7.5),1.22(6H, d, J=6.9), 1.29(3H, t, J=7.4), 1.45–1.52(4H, m), 2.58(2H, s),2.89(2H, q, J=7.4), 3.15(1H, m), 3.77(2H, s), 6.78–6.83(1H, m),7.08–7.21(2H, m), 7.30–7.35(1H, m). I-110 109–111° C. 1.21(6H, d,J=6.9), 1.23(6H, s), 1.25(3H, t, J=7.4), 2.81(2H, q, J=7.4), 2.90(1H, t,J=6.9), 3.05(2H, s), 7.13–7.30(2H, m), 7.36–7.45(2H, m). I-111 1.21(6H,d, J=6.9), 1.31(3H, t, J=7.4), 1.42(3H, d, J=6.7), 2.90(2H, q, J=7.4),3.23(1H, q, J=6.9), 3.69(1H, q, J=6.6), 3.87–3.93(1H, m), 6.78–6.82(1H,m), 7.08–7.20(2H, m), 7.25–7.30(1H, m). I-112 1.19–1.25(9H, m), 1.14(3H,d, J=6.3), 2.76(1H, d, J=10.9), 2.96(2H, t, J=7.4), 3.22(1H, q, J=6.9),3.44–3.48(1H, m), 5.12(1H, q, J=6.3), 6.81–6.85(1H, m), 7.09–7.16(2H,m), 7.28–7.32(1H, m). I-113 126–128° C. 1.18(6H, d, J=6.9), 1.22(6H, d,J=6.9), 1.45(3H, t, J=7.4), 1.80–1.91(1H, m), 2.57–2.64(2H, m), 2.61(3H,s), 2.86–2.89(1H, m), 3.07(1H, m), 5.95–6.05(1H, m), 6.98–7.00(1H, m),7.12–7.22(2H, m), 7.28–7.35(1H, m). I-114 1.20(6H, d, J=6.9), 1.28(3H,d, J=6.9), 1.82–1.88(1H, m), 2.48–2.63(1H, m), 2.63(3H, s), 3.11(1H, m),3.29–3.35(1H, m), 4.26(1H, m), 4.98(1H, m), 6.90–6.95(1H, m),7.15–7.20(2H, m), 7.30–7.35(1H, m). I-115 1.14(3H, d, J=6.5), 1.20(6H,d, J=6.9), 2.53(1H, dd, J=13.0, 5.4), 2.75(3H, s), 2.80–2.85(1H, m),2.95(1H, dd, J=13.0, 5.4), 3.11(1H, m), 3.72(1H, dd, J=13.0, 9.0),5.15(1H, dd, J=13.0, 9.0), 6.90–6.95(1H, m), 7.15–7.25(2H, m),7.30–7.35(1H, m). I-116 119–121° C. 0.88(6H, t, J=7.5), 1.20(6H, d,J=6.9), 1.45–1.52(4H, m), 2.62(2H, s), 2.64(3H, s), 3.15(1H, m),4.66(2H, s), 6.78–6.83(1H, m), 7.08–7.21(2H, m), 7.30–7.35(1H m). I-117 99–100° C. 0.71–0.79(1H, m), 0.85–0.90(2H, m), 1.22(6H, d, J=6.9),1.22–1.25(1H, m), 2.61(3H, s), 2.79(3H, s), 3.00–3.05(1H, m), 4.40(2H,s), 6.92–6.95(1H, m), 7.15–7.21(2H, m), 7.30–7.35(1H, m).

TABLE 24 Comp. No. Physical Date No M.p. I-118 1.23(6H, s), 1.45(6H, t,J=7.4), 2.63(3H, s), 2.67(2H, s), 4.08(2H, q, J=7.0), 4.55(2H, s),6.57–6.63(2H, m), 6.85(1H, d, J=7.9). I-119 116–118° C. 1.24(6H, s),2.37(3H, s), 2.64(3H, s), 2.66(2H, s), 3.84(3H, s), 4.54(2H, s),6.75–6.80(2H, m), 6.88(1H, m). I-120 92–93° C. 1.23(6H, s), 2.27(3H, s),2.63(3H, s), 2.67(2H, s), 3.84(3H, s), 4.51(2H, s), 6.51–6.58(2H, m),7.10(1H, d, J=7.9). I-121 129–130° C. 1.22(6H, s), 2.30(3H, s), 2.63(3H,s), 2.65(2H, s), 3.80(3H, s), 4.53(2H, s), 6.78–6.95(3H, m). I-12293–95° C. 1.22(6H, s), 2.12(3H, s), 2.30(3H, s), 2.64(3H, s), 2.65(2H,s), 4.51(2H, s), 6.76(1H, d, J=7.9), 6.98(1H, d, J=7.9), 7.08(1H, t,J=7.9). I-123 151–152° C. 1.22(6H, s), 1.83(3H, s), 2.63(3H, s),2.65(2H, s), 3.17(3H, s), 4.40(1H, d, J=13.6), 4.65(1H, d, J=13.6),7.01(1H, d, J=7.9), 7.10–7.15(2H, m), 7.30–7.35(1H, m).

TABLE 25 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-124 105–106° C.1.23(6H, s), 1.41(3H, t, J=7.0), 2.63(3H, s), 2.66(2H, s), 4.08(2H, q,J=7.0), 4.50(2H, s), 6.88(2H, d, J=8.6), 6.98(2H, d, J=8.6). I-12592–94° C. 1.23(6H, s), 1.40(3H, t, J=7.0), 2.62(3H, s), 2.66(2H, s),4.08(2H, q, J=7.0), 4.50(2H, s), 6.57–6.63(2H, m), 6.70–6.75(1H, m),7.25–7.30(1H, m). I-126 108–109° C. 1.23(6H, s), 2.63(3H, s), 2.65(2H,s), 3.81(3H, s), 4.50(2H, s), 6.92(2H, d, J=8.6), 7.04(2H, d, J=8.6).I-127 62–64° C. 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 3.82(3H, s),4.50(2H, s), 6.57–6.63(2H, m), 6.70–6.75(1H, m), 7.25–7.30(1H, m). I-12878–79° C. 1.23(6H, s), 1.44(3H, t, J=7.0), 2.59(3H, s), 2.63(2H, s),3.82(3H, s), 4.10(2H, q, J=7.0), 4.47(2H, s), 6.57–6.63(2H, m),6.82–6.87(1H, m). I-129 58–60° C. 1.04(3H, t, J=7.0), 1.23(6H, s),2.00(2H, sext, J=7.0), 2.63(3H, s), 2.67(2H, s), 3.87(3H, s), 4.10(2H,t, J=7.0), 4.50(2H, s), 6.58–6.64(2H, m), 6.86–6.91(1H, m). I-1301.13(6H, s), 1.45(6H, t, J=7.4), 2.28(3H, s), 2.62(2H, s), 3.74(2H, s),4.08(4H, q, J=7.4), 6.46–6.53(2H, m), 6.88–6.92(1H, m). I-131 91–93° C.1.04(3H, t, J=7.0), 1.22(6H, s), 1.76(2H, sext, J=7.0), 2.63(3H, s),2.65(2H, s), 3.91(2H, t, J=7.0), 4.50(2H, s), 6.90(2H, d, J=8.6),6.98(2H, d, J=8.6). I-132 103–104° C. 1.04(3H, t, J=7.0), 1.22(6H, s),1.76(2H, sext, J=7.0), 2.63(3H, s), 2.65(2H, s), 3.91(2H, t, J=7.0),4.50(2H, s), 6.50(1H, d, J=2.1), 6.60(1H, d, J=7.4), 6.72(1H, dd, J=7.4,2.1), 7.28(1H, d, J=7.4). I-133 91–92° C. 0.98(3H, t, J=7.0), 1.23(6H,s), 1.42–1.48(2H, m), 1.70–1.80(2H, m), 2.63(3H, s), 2.65(2H, s),3.96(2H, t, J=7.0), 4.50(2H, s), 6.90(2H, d, J=8.6), 6.98(2H, d, J=8.6).I-134 86–87° C. 0.98(3H, t, J=7.0), 1.23(6H, s), 1.42–1.48(2H, m),1.70–1.80(2H, m), 2.63(3H, s), 2.65(2H, s), 3.96(2H, t, J=7.0), 4.50(2H,s), 6.50(1H, d, J=2.1), 6.60(1H, d, J=7.8), 6.72(1H, dd, J=7.8, 2.1),7.28(1H, d, J=7.8).

TABLE 26 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-135 69–70° C.1.22(6H, s), 1.47(3H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 3.88(3H, s),4.15(2H, q, J=7.0), 4.51(2H, s), 6.61(1H, d, J=8.2), 6.62(1H, d, J=2.1),6.88(1H, d, J=8.2). I-136 88–89° C. 1.04(3H, t, J=7.0), 1.23(6H, s),1.80(2H, sext, J=7.0), 2.63(3H, s), 2.67(2H, s), 3.87(3H, s), 3.90(2H,t, J=7.0), 4.51(2H, s), 6.61(1H, dd, J=8.2, 2.1), 6.62(1H, d, J=2.1),6.88(1H, d, J=8.2). I-137 83–85° C. 0.98(3H, t, J=7.0), 1.23(6H, s),1.42–1.48(2H, m), 1.70–1.80(2H, m), 2.64(3H, s), 2.68(2H, s), 3.87(3H,s), 4.03(2H, t, J=7.0), 4.50(2H, s), 6.59(1H, d, J=8.2), 6.61(1H, s),6.88(1H, d, J=8.2). I-138 84–85° C. 1.23(6H, s), 1.34(6H, d, J=6.1),2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 4.53(1H, sept, J=6.1), 6.89(2H,d, J=8.6), 7.04(2H, d, J=8.6). I-139 92–93° C. 1.23(6H, s), 1.34(6H, d,J=6.1), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s), 4.53(1H, sept, J=6.1),6.50(1H, d, J=2.1), 6.60(1H, d, J=8.0), 6.72(1H, dd, J=8.0, 2.1),7.28(1H, d, J=8.0). I-140 109–110° C. 1.22(6H, s), 2.63(3H, s), 2.65(2H,s), 4.50(2H, s), 7.04(2H, d, J=7.5), 7.15(1H, d, J=7.5), 7.32(2H, t,J=7.5). I-141 92–93° C. 1.23(6H, s), 2.63(3H, s), 2.69(2H, s), 4.54(2H,s), 7.01–7.08(1H, m), 7.11–7.15(3H, m). I-142 133–135° C. 1.23(6H, s),2.63(3H, s), 2.69(2H, s), 4.54(2H, s), 7.03(1H, dd, J=8.0, 2.1),7.08(1H, dd, J=8.0, 2.1), 7.25(1H, t, J=8.0), 7.44(1H, t, J=8.0). I-14392–93° C. 1.23(6H, s), 2.63(3H, s), 2.67(2H, s), 4.50(2H, s), 6.88(1H,dd, J=8.0, 2.1), 7.03(1H, d, J=2.1), 7.15(1H, dd, J=8.0, 2.1), 7.28(1H,t, J=8.0). I-144 134–135° C. 1.22(6H, s), 2.22(3H, s), 2.63(3H, s),2.65(2H, s), 4.50(2H, s), 7.00(1H, d, J=8.1), 7.08(1H, t, J=8.1),7.15–7.25(2H, m). I-145 87–89° C. 1.23(6H, s), 2.37(3H, s), 2.63(3H, s),2.66(2H, s), 4.50(2H, s), 6.82(1H, d, J=8.1), 6.84(1H, s), 6.98(1H, d,J=8.1), 7.21(1H, t, J=8.1).

TABLE 27 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-146 91–93° C.1.23(6H, s), 2.35(3H, s), 2.63(3H, s), 2.65(2H, s), 4.50(2H, s),6.92(2H, d, J=8.6), 7.15(2H, d, J=8.6). I-147 82–83° C. 0.90(3H, t,J=7.0), 1.22(6H, s), 1.28–1.40(2H, m), 1.48–1.55(2H, m), 2.55(2H, t,J=7.0), 2.64(3H, s), 2.66(2H, s), 4.50(2H, s), 6.90(1H, d, J=7.8),7.09(1H, t, J=7.8), 7.11(1H, t, J=7.8), 7.28(1H, d, J=7.8). I-148 72–73°C. 0.90(3H, t, J=7.0), 1.22(6H, s), 1.28–1.40(2H, m), 1.48–1.55(2H, m),2.60(2H, t, J=7.0), 2.64(3H, s), 2.66(2H, s), 4.50(2H, s), 6.95(2H, d,J=8.6), 7.18(2H, d, J=8.6). I-149 133–134° C. 1.23(6H, s), 1.35(9H, s),2.65(3H, s), 2.69(2H, s), 4.50(2H, s), 6.97(1H, d, J=7.8), 7.13(1H, t,J=7.8), 7.19(1H, t, J=7.8), 7.41(1H, d, J=7.8). I-150  99–100° C.1.22(6H, s), 1.23(3H, t, J=7.4), 2.62(3H, s), 2.64(2H, s), 2.66(2H, q,J=7.4), 4.50(2H, s), 6.95(2H, d, J=8.6), 7.20(2H, d, J=8.6). I-15140–42° C. 1.23(6H, s), 1.24(3H, t, J=7.0), 2.64(3H, s), 2.66(2H, s),2.67(2H, q, J=7.0), 4.52(2H, s), 6.83(1H, d, J=8.1), 6.86(1H, s),7.00(1H, d, J=8.1), 7.28(1H, t, J=8.1). I-152 118–119° C. 1.23(6H, s),2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 6.97–7.10(4H, m). I-153 89–90° C.1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 6.73–6.90(3H, m),7.25–7.30(1H, m). I-154 111–112° C. 1.22(6H, s), 1.25(6H, d, J=7.0),2.62(3H, s), 2.64(2H, s), 2.91(1H, sept, J=7.0), 4.50(2H, s), 6.95(2H,d, J=8.6), 7.25(2H, d, J=8.6). I-155 127–129° C. 1.23(6H, s), 2.62(3H,s), 2.64(2H, s), 3.14–3.18(4H, m), 3.85–3.90(4H, m), 4.50(2H, s),6.93(2H, d, J=8.6), 7.04(2H, d, J=8.6). I-156 91–93° C. 1.24(6H, s),2.62(3H, s), 2.65(3H, s), 2.68(2H, s), 4.53(2H, s), 7.21–7.25(1H, m),7.48(1H, t, J=7.9), 7.61(1H, t, J=1.8), 7.74–7.78(1H, m).

TABLE 28 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-157 103.5–104.5°C. 1.23(6H, s), 2.63(3H, s), 2.68(2H, s), 4.50(2H, s), 6.88–6.94(2H, m),7.46–7.51(2H, m). I-158 97–98° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H, s),4.51(2H, s), 6.93–6.97(1H, m), 7.19–7.31(3H, m). I-159 155.5–156.5° C.1.24(6H, s), 2.65(3H, s), 2.69(2H, s), 4.54(2H, s), 6.98–7.05(2H, m),7.28–7.34(1H, m), 7.59–7.63(1H, m). I-160 102–106° C. 1.23(6H, s),2.23(3H, s), 2.64(3H, s), 2.67(2H, s), 4.00(3H, s), 4.52(2H, s),7.01–7.05(1H, m), 7.28(1H, t, J=1.8), 7.37(1H, t, J=7.8), 7.45–7.49(1H,m). I-161 111–112° C. 1.23(6H, s), 2.60(3H, s), 2.65(3H, s), 2.69(2H,s), 4.53(2H, s), 7.06–7.10(2H, m), 7.97–8.03(2H, m). I-162 124–125° C.1.23(6H, s), 2.23(3H, s), 2.64(3H, s), 2.67(2H, s), 4.00(3H, s),4.52(2H, s), 7.00–7.05(2H, m), 7.65–7.70(2H, m). I-163   102–103.5° C.1.23(6H, s), 1.32(6H, d, J=6.3), 2.63(2H, s), 2.64(3H, s), 4.52(2H, s),4.52(1H, sept, J=6.3), 6.90–6.98(3H, m), 7.04–7.13(1H, m) I-164 90–92°C. 0.94(3H, t, J=7.3), 1.23(6H, s), 1.58(2H, sext, J=7.3), 2.51–2.56(2H,m), 2.65(3H, s), 2.65(2H, s), 4.51(2H, s), 6.90(1H, dd, J=7.6, 1.3),7.07–7.25(3H, m) I-165 157–158° C. 1.23(6H, s), 2.64(3H, s), 2.68(2H,s), 4.49(2H, s), 7.08(1H, d, J=7.9), 7.22(1H, d, J=7.6), 7.50–7.56(1H,m), 7.66–7.69(1H, m) I-166 145–146° C. 1.24(6H, s), 2.64(3H, s),2.69(2H, s), 4.51(2H, s), 7.00–7.13(7H, m), 7.30–7.37(2H, m) I-16777–79° C. 0.95(3H, t, J=7.3), 1.23(6H, s), 1.65(2H, sext, J=7.3),2.58(2H, t, J=7.3), 2.63(3H, s), 2.66(2H, s), 4.51(2H, s), 6.93–7.00(2H,m), 7.14–7.20(2H, m)

TABLE 29 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-168 117–118° C.1.23(6H, s), 1.55(9H, s), 2.63(3H, s), 2.67(2H, s), 4.52(2H, s),6.96–7.01(2H, m), 7.37–7.42(2H, m). I-169 55–56° C. 1.24(6H, s),2.65(3H, s), 2.69(2H, s), 4.53(2H, s), 7.19(1H, d, J=7.6), 7.26–7.27(1H,m), 7.40–7.52(2H, m). I-170 88–90° C. 1.24(6H, s), 2.65(3H, s), 2.69(2H,s), 4.53(2H, s), 7.10(2H, d, J=8.2), 7.63(2H, d, J=8.2). I-171 1.15(6H,s), 1.18(6H, d, J=6.9), 2.17(3H, s), 2.31(3H, s), 2.64(2H, s), 3.11(1H,sept, J=6.9), 3.78(2H, s), 6.80(1H, d, J=8.2), 7.11–7.18(1H, m),7.28–7.35(1H, m). I-172 1.15(6H, s), 1.18(6H, d, J=6.9), 2.15(3H, s),2.31(3H, s), 2.65(2H, s), 3.11(1H, sept, J=6.9), 3.78(2H, s), 6.99(1H,s), 7.11–7.18(1H, m), 7.28–7.35(1H, s). I-173 121–123° C. 1.22(6H, s),2.64(3H, s), 2.67(2H, s), 3.89(3H, s), 3.89(3H, s), 4.54(2H, s),6.96(1H, d, J=8.6), 7.67(1H, d, J=2.1), 7.87(1H, dd, J=8.6, 2.1). I-174146–147° C. 1.24(6H, s), 2.59(2H, s), 2.65(3H, s), 2.96–2.99(4H, m),3.76–3.79(4H, m), 4.52(2H, s), 6.98–7.17(4H, m). I-175 155–157° C.1.23(6H, s), 2.64(3H, s), 2.66(2H, s), 3.16–3.20(4H, m), 3.84–3.88(4H,m), 4.51(2H, s), 6.54–6.57(2H, m), 6.70–6.74(1H, m), 7.24–7.30(1H, m).I-176 1.22(6H, d, J=6.6), 1.23(6H, s), 1.38(3H, t, J=7.1), 2.65(3H, s),2.67(2H, s), 3.08–3.18(1H, m), 4.37(2H, q, J=6.9), 4.52(2H, s), 7.38(1H,d, J=7.9), 7.59(1H, d, J=2.0), 7.82(1H, dd, J=8.1, 1.8). I-177 120–122°C. 1.23(6H, s), 1.50–1.61(2H, m), 1.67–1.75(4H, m), 2.62(3H, s),2.66(2H, s), 3.13–3.17(4H, m), 4.50(2H, s), 6.92–7.02(4H, m). I-178124–125° C. 1.23(6H, s), 1.85–1.90(4H, m), 2.62(3H, s), 2.68(2H, s),3.22–3.27(4H, m), 4.48(2H, s), 6.74–6.80(2H, m), 6.95–6.98(1H, m),7.03–7.10(1H, m).

TABLE 30 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-179 1.23(6H, s),2.50(3H, s), 2.64(3H, s), 2.67(2H, s), 4.51(2H, s), 6.78–6.82(1H, m),6.91(1H, t, J=2.0), 7.03–7.07(1H, m), 7.25–7.31(1H, m). I-180 102–103°C. 1.23(6H, s), 2.49(3H, s), 2.63(3H, s), 2.67(2H, s), 4.51(2H, s),6.96–7.01(2H, m), 7.27–7.31(2H, m). I-181 82–83° C. 1.23(6H, s),2.64(3H, s), 2.67(2H, s), 4.52(2H, s), 7.07(1H, dd, J=7.6, 1.7),7.14–7.20(1H, m), 7.25–7.34(2H, m). I-182 1.23(6H, s), 2.64(3H, s),2.69(2H, s), 4.52(2H, s), 6.90(1H, s), 6.93–7.04(2H, m), 7.38(1H, t,J=8.2) I-183 68–70° C. 1.24(6H, s), 2.64(3H, s), 2.69(2H, s), 4.51(2H,s), 7.01–7.07(2H, m), 7.21–7.24(2H, m). I-184 169–170° C. 1.25(6H, s),2.66(3H, s), 2.70(2H, s), 4.54(2H, s), 7.13–7.18(2H, m), 7.34–7.39(1H,m), 7.59–7.63(2H, m), 7.86–7.91(1H, m), 8.58(1H, dd, J=4.8, 1.6),8.87(1H, t, J=1.5) I-185 92.5–93.5° C. 1.24(6H, s), 2.65(3H, s),2.69(2H, s), 4.54(2H, s), 7.05–7.09(1H, m), 7.24(1H, t, J=1.6),7.34–7.40(2H, m), 7.49(1H, t, J=7.6), 7.87–7.92(1H, m), 8.60(1H, dd,J=4.9, 1.4), 8.87(1H, dd, J=2.3, 0.7) I-186 1.09(6H, s), 2.56(3H, s),2.58(2H, s), 4.20(2H, s), 7.09–7.12(1H, m), 7.24–7.30(2H, m),7.36–7.45(2H, m), 7.75–7.79 (1H, m), 8.54(1H, dd, J=4.9, 1.6), 8.68(1H,dd, J=2.3, 0.7) I-187 110.5–111.5° C. 1.17(6H, s), 2.51(3H, s), 2.61(2H,s), 4.33(2H, s), 6.93–7.19(7H, m), 7.23–7.30(2H, m) I-188 75–76° C.1.14(6H, s), 1.43(6H, t, J=7.4), 2.61(2H, s), 3.65(2H, s), 3.84(3H, s),4.08(4H, q, J=7.4), 6.46(1H, dd, J=8.1, 2.2), 6.52(1H, d, J=2.2),6.84(1H, d, J=8.4). I-189 1.19(6H, s), 2.61(2H, s), 3.65(2H, s),3.85(3H, s), 3.88(3H, s), 6.85–6.99(3H, m), 7.02–7.15(1H, m).

TABLE 31 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-190 1.13(6H, s),1.23(3H, t, J=7.4), 2.62(2H, s), 2.66(2H, q, J=7.4), 3.64(2H, s),3.84(3H, s), 6.84(2H, d, J=8.6), 7.16(2H, d, J=8.6). I-191 45–47° C.1.14(6H, s), 1.25(6H, d, J=7.0), 2.62(2H, s), 2.91(1H, sept, J=7.0),3.64(2H, s), 3.84(3H, s), 6.86(2H, d, J=8.6), 7.19(2H, d, J=8.6). I-19293–95° C. 1.15(6H, s), 2.31(3H, s), 2.62(2H, s), 3.80(2H, s), 3.85(3H,s), 6.85–6.99(3H, m), 7.02–7.15(1H, m). I-193 65–67° C. 1.13(6H, s),1.23(3H, t, J=7.4), 2.31(3H, s), 2.62(2H, s), 2.65(2H, q, J=7.4),3.77(2H, s), 6.90(2H, d, J=8.3), 7.21(2H, d, J=8.3). I-194 95–97° C.1.15(6H, s), 1.24(6H, d, J=7.0), 2.31(3H, s), 2.64(2H, s), 2.91(1H,sept, J=7.0), 3.77(2H, s), 6.90(2H, d, J=8.6), 7.21(2H, d, J=8.6). I-19594–96° C. 1.15(6H, s), 1.41(3H, t, J=7.0), 2.31(3H, s), 2.64(2H, s),3.77(2H, s), 4.05(2H, q, J=7.4), 6.90–6.99(4H, m). I-196  99–100° C.1.15(6H, s), 1.47(3H, t, J=7.0), 2.32(3H, s), 2.66(2H, s), 3.77(2H, s),3.88(3H, s), 4.08(2H, q, J=7.0), 6.52(1H, d, J=8.2), 6.56(1H, d, J=2.1),6.88(1H, d, J=8.2). I-197 133–134° C. 1.23(6H, s), 1.50–1.75(6H, m),2.63(3H, s), 2.65(2H, s), 3.18(4H, t, J=5.4), 4.51(2H, s), 6.47–6.57(2H,m), 6.72–6.76(1H, m), 7.21(1H, d, J=8.1) I-198 124–125° C. 1.17(6H, t,J=6.9), 1.23(6H, s), 2.61(3H, s), 2.68(2H, s), 3.35(4H, q, J=6.9),4.49(2H, s), 6.68(2H, d, J=8.9), 7.04(2H, d, J=8.9) I-199 85–87° C.1.22(6H, s), 2.63(3H, s), 2.67(2H, s), 3.89(3H, s), 3.92(3H, s),4.54(2H, s), 7.01(1H, d, J=7.9), 7.62(1H, d, J=1.3), 7.67(1H, dd, J=7.9,1.7) I-200 137–138° C. 1.23(6H, s), 2.11–2.22(2H, m), 2.62(2H, t,J=7.9), 2.64(3H, s), 2.67(2H, s), 3.88(2H, t, J=7.1), 4.52(2H, s),6.81–6.84(1H, m), 7.30–7.50(3H, m)

TABLE 32 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-201 86.5–87.5° C.1.22(6H, s), 2.62(3H, s), 2.67(2H, s), 4.50(2H, s), 6.71(1H, t, J=2.0),6.76–6.82(2H, m), 7.02–7.13(3H, m), 7.29–7.37(3H, m) I-202 162–163° C.1.25(6H, s), 2.65(3H, s), 2.70(2H, s), 4.54(2H, s), 7.10–7.14(2H, m),7.33–7.46(3H, m), 7.59–7.63(4H, m) I-203 56.5–57.5° C. 1.06(6H, s),2.51(3H, s), 2.59(2H, s), 4.14(2H, s), 7.07(1H, dd, J=8.2, 1.3),7.21–7.45(8H, m) I-204 97–99° C. 1.24(6H, s), 2.65(3H, s), 2.68(2H, s),4.54(2H, s), 7.00–7.04(1H, m), 7.25–7.26(1H, m), 7.33–7.48(5H, m),7.60–7.63(2H, m) I-205 95–96° C. 1.21(6H, s), 1.21(6H, d, J=6.9),2.61(2H, s), 4.13(3H, s), 4.16(2H, s), 6.77–6.81(1H, m), 7.13–7.16(2H,m), 7.29–7.33(1H, m) I-206 128–129° C. 1.18(6H, d, J=6.9), 1.22(6H, s),2.63(3H, s), 2.66(2H, s), 2.96–3.06(1H, m), 4.48(2H, s), 6.67(1H, d,J=8.2), 7.47(1H, dd, J=8.2, 1.7), 7.59(1H, d, J=2.0) I-207 149–150° C.1.23(6H, s), 2.63(3H, s), 2.67(2H, s), 3.71(8H, m), 3.86(3H, s),4.53(2H, s), 6.95–7.05(3H, m) I-208 124–126° C. 1.23(6H, s), 2.61(3H,s), 2.67(2H, s), 2.96(6H, s), 4.50(2H, s), 6.74(2H, d, J=8.2), 7.04(2H,d, J=8.2). I-209 107–109° C. 1.23(6H, s), 2.63(3H, s), 2.65(2H, s),2.96(6H, s), 4.51(2H, s), 6.34(1H, d, J=2.0), 6.38(1H, d, J=8.0),6.54(1H, dd, J=8.0, 2.0), 7.24(2H, d, J=8.0). I-210 98–99° C. 1.06(3H,t, J=7.4), 1.23(6H, s), 2.63(5H, s), 2.65(3H, s), 2.99(2H, q, J=7.4),4.51(2H, s), 6.98–7.10(3H, m), 7.15–7.20(1H, m). I-211 94–96° C.0.84(3H, t, J=7.4), 1.22(6H, s), 1.49(2H, sext, J=7.3), 2.63(3H, s),2.65(2H, s), 2.72(3H, s), 2.84(2H, t, J=7.4), 4.51(2H, s), 6.90–7.05(3H,m), 7.10–7.15(1H, m).

TABLE 33 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-212 98–99° C.1.02(6H, t, J=7.4), 1.22(6H, s), 2.61(2H, s), 2.63 (3H, s), 3.06(4H, q,J=7.4), 4.51(2H, s), 6.98–7.10(4H, m). I-213 83–84° C. 1.23(6H, s),2.64(3H, s), 2.71(2H, s), 4.57(2H, s), 6.90–7.12(3H, m) I-214 1.19(6H,d, J=6.9), 1.23(6H, s), 2.64(3H, s), 2.67(2H, s), 3.06(1H, sept, J=6.9),4.49(2H, s), 6.85(1H, d, J=8.2), 7.14(1H, dd, J=8.2, 2.3), 7.27(1H, d,J=2.3) I-215 83–85° C. 1.23(6H, s), 2.32(3H, s), 2.63(3H, s), 2.66(2H,s), 2.71(6H, s), 4.50(2H, s), 6.75–6.80(1H, m), 6.98(1H, s),6.97–7.00(1H, m). I-216  99–100° C. 1.23(6H, s), 2.33(3H, s), 2.62(3H,s), 2.65(2H, s), 2.70(6H, s), 4.50(2H, s), 6.78(2H, t, J=7.9), 6.91(1H,d, J=7.9). I-217 98–99° C. 1.23(6H, s), 2.30(3H, s), 2.63(3H, s),2.64(2H, s), 2.67(6H, s), 4.50(2H, s), 6.81(1H, s), 6.92(2H, s). I-218117–19° C.  1.23(6H, s), 2.63(3H, s), 2.65(2H, s), 2.68(6H, s), 4.50(2H,s), 6.89(1H, d, J=8.5), 6.99(1H, d, J=2.0), 7.04(1H, dd, J=7.9, 2.0).I-219 68–70° C. 1.22(6H, s), 2.22(6H, s), 2.64(3H, s), 2.66(2H, s),4.54(2H, s), 6.93–6.98(1H, m), 7.04(2H, d, J=8.0). I-220 97–99° C.1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.72(6H, s), 3.25(2H, q,J=7.4), 4.47(2H, s), 6.94–7.05(3H, m), 7.15–7.20(1H, m). I-221 118–119°C. 1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.95(6H, s), 3.25(2H,q, J=7.4), 4.47(2H, s), 6.34(1H, d, J=7.5), 6.38(1H, s), 6.52(1H, d,J=7.5), 7.24(1H, t, J=7.5). I-222 74–76° C. 1.22(6H, s), 1.34(3H, t,J=7.4), 2.33(3H, s), 2.63(2H, s), 2.70(6H, s), 3.25(2H, q, J=7.4),4.47(2H, s), 6.78(1H, d, J=7.5), 6.82(1H, s), 6.91(1H, t, J=7.5).

TABLE 34 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-223 1.22(6H, s),1.25(6H, d, J=7.0), 1.34(3H, t, J=7.4), 2.65(2H, s), 2.91(1H, sept,J=7.0), 3.25(2H, q, J=7.4), 4.50(2H, s), 6.98(2H, d, J=8.2), 7.28(2H, d,J=8.2). I-224 1.21(6H, s), 2.62(3H, s), 2.66(2H, s), 2.97(3H, d, J=4.9),3.84(3H, s), 4.51(2H, s), 6.66(1H, brs), 6.96(1H, d, J=7.9),7.30–7.33(1H, m), 7.49(1H, d, J=1.3) I-225 69–71° C. 1.23(6H, s),2.64(3H, s), 2.68(2H, s), 4.52(2H, s), 6.49(1H, t, J=74.6),7.04–7.26(4H, m) I-226 1.23(6H, s), 2.64(3H, s), 2.68(2H, s), 4.51(2H,s), 6.50(1H, t, J=74.2), 7.00–7.05(2H, s), 7.11–7.16(2H, m) I-227 81–83°C. 1.17(6H, t, J=7.0), 1.23(6H, s), 2.63(3H, s), 2.66(2H, s), 3.35(4H,q, J=7.0), 4.52(2H, s), 6.29(1H, s), 6.30(1H, dt, J=8.2, 2.3), 6.49(1H,dd, J=8.2, 2.3), 7.19(1H, t, J=8.2). I-228 106–107° C. 1.21(6H, s),2.61(3H, s), 2.64(2H, s), 2.70(6H, s), 4.47(2H, s), 6.90(2H, s),6.93(1H, s). I-229 121–122° C. 1.23(6H, s), 2.62(3H, s), 2.65(2H, s),2.70(6H, s), 4.48(2H, s), 6.50–6.70(2H, m), 6.93(1H, dd, J=8.5, 6.2).I-230 85–86° C. 1.21(6H, s), 2.63(3H, s), 2.64(2H, s), 2.66(6H, s),4.49(2H, s), 6.74–6.79(2H, m), 6.93–6.98(1H, m). I-231 82–84° C.1.23(6H, s), 1.25(3H, t, J=7.6), 2.62(3H, s), 2.66(2H, s), 2.67(2H, q,J=7.6), 2.71(6H, s), 4.50(2H, s), 6.80(1H, d, J=7.6), 6.84(1H, s),6.93(1H, d, J=7.6). I-232 75–76° C. 1.22(3H, t, J=7.6), 1.23(6H, s),2.60(2H, q, J=7.6), 2.63(3H, s), 2.64(2H, s), 2.68(6H, s), 4.50(2H, s),6.83(1H, s), 6.93(2H, s). I-233 86–88° C. 1.22(6H, s), 1.33(3H, t,J=7.4), 2.64(2H, s), 2.71(6H, s), 3.24(2H, q, J=7.4), 4.47(2H, s),6.92(2H, s), 6.94(1H, s).

TABLE 35 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-234 70–71° C.1.22(6H, s), 1.34(3H, t, J=7.4), 2.64(2H, s), 2.71(6H, s), 3.25(2H, q,J=7.4), 4.46(2H, s), 6.60–6.68(2H, m), 6.92–6.94(1H, m). I-235 80–82° C.1.22(6H, s), 1.24(3H, t, J=7.6), 1.33(3H, t, J=7.4), 2.60(2H, q, J=7.6),2.61(2H, s), 2.71(6H, s), 3.24(2H, q, J=7.4), 4.47(2H, s), 6.81(1H, d,J=7.6), 6.94(1H, s), 6.94(1H, d, J=7.6). I-236 1.03(3H, t, J=7.3),1.20(6H, d, J=6.9), 1.23(6H, s), 1.40(3H, d, J=6.9), 1.61–1.89(2H, m),2.63(2H, s), 3.15(1H, sept, J=6.9), 3.95(1H, q, J=6.9), 4.47(2H, s),6.89–6.92(1H, m), 7.13–7.20(2H, m), 7.31–7.34(1H, m) I-237 1.05(6H, d,J=6.6), 1.21(6H, d, J=6.6), 1.23(6H, s), 1.98–2.08(1H, m), 2.64(2H, s),3.16(1H, sept, J=6.6), 3.20(2H, d, J=6.6), 4.49(2H, s), 6.88–6.92(1H,m), 7.13–7.22(2H, m), 7.30–7.35(1H, m) I-238 102–104° C. 1.20(6H, d,J=6.9), 1.22(6H, s), 2.61(2H, s), 2.85–2.95(1H, m), 3.19(3H, d, J=4.6),4.46(2H, s), 6.73–6.79(1H, m), 7.14–7.20(2H, m), 7.29–7.34(1H, m),12.40(1H, brs) I-239 58–60° C. 1.23(6H, s), 2.17(3H, s), 2.64(3H, s),2.65(2H, s), 2.70(6H, s), 4.52(2H, s), 6.63(1H, d, J=7.9), 6.87(1H, d,J=7.9), 7.14(1H, d, J=7.9). I-240 100–101° C. 1.23(6H, s), 2.62(3H, s),2.64(2H, s), 2.78(6H, s), 3.89(3H, s), 4.52(2H, s), 6.60–6.70(2H, m),6.94(1H, d, J=7.9). I-241 82–83° C. 1.23(6H, s), 2.30(3H, s), 2.63(3H,s), 2.65(2H, s), 2.70(6H, s), 4.52(2H, s), 6.63(1H, dt, J=7.9, 1.9),6.70(1H, d, J=1.9), 7.14(1H, d, J=7.9). I-242  99–100° C. 1.23(6H, s),2.63(3H, s), 2.68(2H, s), 2.81(6H, s), 4.50(2H, s), 6.91(1H, dt, J=8.4,2.6), 7.06(1H, d, J=8.4), 7.14(1H, d, J=2.6). I-243 63–64° C. 1.23(6H,s), 2.63(3H, s), 2.67(2H, s), 2.78(6H, s), 3.89(3H, s), 4.52(2H, s),6.67(1H, s), 6.70(1H, d, J=7.9), 6.81(1H, d, J=7.9). I-244 68–70° C.0.88(6H, t, J=7.5), 1.22(6H, d, J=6.9), 1.35(3H, t, J=7.4),1.50–1.70(4H, m), 2.61(2H, s), 3.15(1H, sept, J=6.9), 3.29(2H, q,J=7.4), 4.44(2H, s), 6.89–6.92(1H, m), 7.08–7.21(2H, m), 7.30–7.35(1H,m).

TABLE 36 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-245 81–82° C.1.14(6H, s), 1.20(6H, d, J=6.9), 2.63(2H, s), 3.06(2H, s), 3.08(1H,sept, J=6.9), 3.18(3H, s), 6.74(1H, dd, J=7.3, 1.7), 6.98–7.10(2H, m),7.20–7.24(1H, m) I-246 47–49° C. 0.95(3H, t, J=7.3), 1.13(6H, s),1.20(6H, d, J=6.9), 1.55–1.74(2H, m), 2.62(2H, s), 3.03–3.11(3H, m),3.52–3.57(2H, m), 6.73(1H, dd, J=7.6, 1.7), 6.96–7.10(2H, m), 7.21(1H,dd, J=7.3, 1.7) I-247 68–70° C. 1.11(6H, s), 1.18(6H, d, J=6.9),1.19(6H, d, J=6.9), 2.56(2H, s), 2.89(2H, s), 3.08(1H, sept, J=6.9),5.08(1H, sept, J=6.9), 6.73(1H, dd, J=7.9, 1.7), 6.99–7.10(2H, m),7.21(1H, dd, J=7.9, 1.7) I-248 0.97(6H, d, J=6.9), 1.14(6H, s), 1.18(6H,d, J=6.9), 2.05–2.15(1H, m), 2.62(2H, s), 3.07(2H, s), 3.08(1H, sept,J=6.9), 3.44(2H, d, J=7.6), 6.71(1H, dd, J=7.6, 1.7), 6.96–7.09(2H, m),7.21(1H, dd, J=7.6, 1.7) I-249 96–97° C. 1.23(6H, s), 2.64(3H, s),2.68(2H, s), 4.59(2H, s), 7.04(1H, d, J=7.3), 7.41–7.50(3H, m), 7.67(1H,d, J=7.3), 7.87(1H, dd, J=7.3, 2.1), 8.05(1H, d, J=7.3). I-250 108–109°C. 1.24(6H, s), 2.67(3H, s), 2.69(2H, s), 4.59(2H, s), 7.15(1H, d,J=7.3), 7.41(1H, q, J=7.3), 7.69(1H, t, J=8.4), 7.91(1H, d, J=7.3),8.45(1H, d, J=8.4), 8.92–8.95(1H, m). I-251 105–107° C. 1.22(6H, s),2.62(3H, s), 2.65(2H, s), 3.97(3H, s), 4.53(2H, s), 6.87–6.90(1H, m),7.25–7.30(1H, m), 7.96–7.99(1H, m). I-252 132–133° C. 1.23(6H, s),2.63(3H, s), 2.68(2H, s), 2.92(3H, s), 4.49(2H, s), 6.73–6.78(1H, m),7.20–7.23(1H, m), 8.05–8.07(1H, m) I-253 118–120° C. 1.23(6H, s),2.60(3H, s), 2.63(2H, s), 4.52(2H, s), 7.30(2H, s), 8.12(1H, s). I-254112–113° C. 1.23(6H, s), 2.63(3H, s), 2.69(2H, s), 3.94(3H, s), 4.51(2H,s), 6.76(1H, d, J=8.1), 7.35(1H, dd, J=8.1, 2.1), 7.92(1H, d, J=2.1).I-255 109–110° C. 1.23(6H, s), 1.40(3H, t, J=7.0), 2.62(3H, s), 2.66(2H,s), 4.38(2H, q, J=7.0), 4.51(2H, s), 6.75(1H, d, J= 8.1). 7.35(1H, dd,J=8.1, 2.1), 7.90(1H, d, J=2.1).

TABLE 37 Physical Date No M.p. NMR(CHCl₃) I-256 75–76° C. 1.03(3H, t,J=7.6), 1.22(6H, s), 1.76(2H, sext, J=7.6), 2.63(3H, s), 2.65(2H, s),4.24(2H, t, J=7.6), 4.51(2H, s), 6.76(1H, d, J=8.1), 7.35(1H, dd, J=8.1,2.1), 7.92(1H, d, J=2.1). I-257 74–76° C. 1.24(6H, s), 1.36(6H, d,J=6.3), 2.63(3H, s), 2.70(2H, s), 4.51(2H, s), 5.28(1H, sept, J=6.3),6.70(1H, d, J=8.1), 7.32(1H, dd, J=8.1, 2.1), 7.92(1H, d, J=2.1). I-258102–104° C. 1.23(6H, s), 2.58(3H, s), 2.63(2H, s), 2.69(3H, s), 4.51(2H,s), 7.20–7.26(2H, m), 8.21(1H, d, J=2.1). I-259 81–83° C. 1.23(6H, s),1.38(3H, t, J=7.3), 2.63(3H, s), 2.63(2H, s), 3.18(2H, q, J=7.3),4.51(2H, s), 7.15–7.26(2H, m), 8.21(1H, d, J=2.1). I-260 78–79° C.1.05(3H, t, J=7.4), 1.23(6H, s), 1.75(2H, sext, J=7.3), 2.63(3H, s),2.65(2H, s), 3.15(2H, t, J=7.4), 4.51(2H, s), 7.15–7.26(2H, m), 8.20(1H,d, J=2.1). I-261 102–103° C. 1.23(6H, s), 1.40(6H, d, J=6.6), 2.63(3H,s), 2.66(2H, s), 4.00(1H, sept, J=6.6), 4.51(2H, s), 7.15–7.26(2H, m),8.22(1H, d, J=2.1). I-262 109–110° C. 1.22(6H, s), 2.61(3H, s), 2.65(2H,s), 2.70(6H, s), 3.80(3H, s), 4.48(2H, s), 6.47(1H, dd, J=7.9, 2.1),6.56(1H, d, J=2.1), 6.95(1H, d, J=7.9). I-263  99–100° C. 1.22(6H, s),2.62(3H, s), 2.63(2H, s), 2.64(6H, s), 3.78(3H, s), 4.48(2H, s),6.59(1H, d, J=2.1), 6.64(1H, dd, J=7.9, 2.1), 6.98(1H, d, J=7.9). I-264114–115° C. 0.98(6H, t, J=7.0), 1.23(6H, s), 2.16(3H, s), 2.63(3H, s),2.64(2H, s), 2.98(4H, q, J=7.0), 4.52(2H, s), 6.65(1H, d, J=7.9),6.89(1H, d, J=7.9), 7.13(1H, t, J=7.9). I-265 66–67° C. 0.98(6H, t,J=7.0), 1.23(6H, s), 2.16(3H, s), 2.63(3H, s), 2.64(2H, s), 2.98(4H, q,J=7.0), 4.52(2H, s), 6.63(1H, dd, J=7.9, 2.1), 6.70(1H, d, J=2.1),7.16(1H, d, J=7.9). I-266 88–90° C. 1.04(6H, t, J=7.0), 1.24(6H, s),2.63(3H, s), 2.67(2H, s), 3.17(4H, q, J=7.0), 3.86(3H, s), 4.51(2H, s),6.67(1H, s), 6.70(1H, d, J=7.9), 6.85(1H, d, J=7.9).

TABLE 38 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-267 138–140° C.0.82–0.92(9H, m), 1.18(3H, d, J=6.9), 1.51–1.65(6H, m), 2.62(2H, s),2.65(3H, s), 2.87(1H, sept, J=6.9), 4.33(1H, d, J=13.5), 4.59(1H, d,J=13.5), 6.89–6.92(1H, m), 7.13–7.28(3H, m) I-268 161–163° C.0.89–0.95(6H, m), 1.21(6H, d, J=6.9), 1.25–1.54(8H, m), 2.62(2H, s),2.65(3H, s), 3.10(1H, sept, J=6.9), 4.47(2H, s), 6.88–6.92(1H, m),7.14–7.18(2H, m), 7.31–7.34(1H, m) I-269 1.21(6H, d, J=6.9),1.65–1.88(8H, m), 2.64(3H, s), 2.75(2H, s), 3.09(1H, sept, J=6.9),4.57(2H, s), 6.90–6.94(1H, m), 7.13–7.20(2H, m), 7.30–7.35(1H, m) I-2701.21(6H, d, J=6.9), 1.37–1.54(8H, m), 1.76–1.80(2H, m), 2.65(3H, s),2.67(2H, s), 3.09(1H, sept, J=6.9), 4.54(2H, s), 6.89(1H, m),7.11–7.21(2H, m), 7.29–7.34(1H, m)

TABLE 39 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-271 1.04(3H, s),1.08(3H, s), 1.29(6H, d), J=6.9), 2.69(2H, s), 3.40(1H, sept, J=6.9),3.43(3H, s), 3.51(2H, s), 7.18–7.29(2H, m), 7.36–7.45(2H, m) I-2720.96(3H, s), 1.05(3H, s), 1.25(3H, d, J=6.9), 1.26(3H, d, J=6.9),2.61(1H, d, J=12), 2.70(1H, d, J=12), 3.39(1H, sept, J=6.9),3.45–3.58(2H, m), 7.02–7.07(2H, m), 7.11–7.18(1H, m), 7.38–7.45(2H, m),7.61–7.70(2H, m) I-273 0.84(3H, s), 1.00(3H, s), 1.25(3H, d, J=6.9),1.29(3H, J=6.9), 2.43(3H, s), 2.53(1H, d, J=12), 2.64(1H, d, J=12),3.29(1H, d, J=16), 3.42(1H, d, J=16), 3.47(1H, sept, J=6.9),7.09–7.19(2H, m), 7.24–7.29(2H, m), 7.38–7.45(2H, m), 7.81–7.86(2H, m)I-274 0.99(6H, s), 1.19(6H, d, J=6.9), 2.40(3H, s), 2.67(2H, s),2.87(1H, sept, J=6.9), 3.43(2H, s), 7.11–7.29(6H, m), 7.68(2H, d, J=8.1)I-275 1.07(6H, s), 1.26(6H, d, J=6.9), 1.38(3H, t, J=7.2), 2.71(2H, s),2.93(1H, sept, J=6.9), 3.51(2H, s), 3.60(2H, q, J=7.2), 7.20–7.30(4H, m)I-276 1.19(6H, s), 1.23(6H, d, J=6.9), 2.77(2H, s), 2.87(1H, sept,J=6.9), 3.58(2H, s), 6.65–6.69(2H, m), 6.91(1H, d, J=7.5), 7.20(1H, t,J=7.5), 7.51(2H, d, J=9.3), 8.22(2H, d, J=9.3) I-277 0.99(6H, s),1.20(6H, d, J=6.9), 2.67(2H, s), 2.88(1H, sept, J=6.9), 3.44(2H, s),3.85(3H, s), 6.86–6.90(2H, m), 7.11–7.26(4H, m), 7.72–7.76(2H, m)

TABLE 40 Comp. No. Physical Date No M.p. NMR(CHCl₃) I-278 1.03(6H, s),1.20(6H, d, J=6.9), 2.70(2H, s), 2.88(1H, sept, J=6.9), 3.44(2H, s),7.08–7.31(4H, m), 7.60(1H, t, J=8.4), 8.04(1H, d, J=8.4), 8.39(d,J=8.4), 8.74(1H, s) I-279 1.01(6H, s), 1.19(6H, d, J=6.9), 2.69(2H, s),2.88(1H, sept, J=6.9), 3.42(2H, s), 7.09–7.32(4H, m), 7.68(2H, d,J=8.4), 7.92(2H, d, J=8.4), I-280 1.19(3H, s), 1.21(3H, s),1.23–1.30(6H, m), 2.62(1H, d, J=12), 2.82(1H, sept, J=6.9), 3.02(1H, d,J=12), 3.46–3.70 (2H, m), 6.53–6.60(2H, m), 6.86(1H, d, J=7.8), 7.13(1H,t, J=7.8), 7.28–7.40(2H, m), 7.61–7.66(1H, m), 7.90(1H, dd, J=7.5, 1.2)

The following compounds are within the scope of the present invention.These compounds can be prepared in accordance with the above examples.

The numbers of left column in Table represent Compound No.

TABLE 41-A

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ A-1  H Pr H H H CSSMe Me Me A-2  Pr^(i) H Cl H HCSSMe Me Me A-3  H Bu^(s) H H H CSSMe Me Me A-4  H H Bu^(s) H H CSSMe MeMe A-5  OPr H H H H CSSMe Me Me A-6  OBu H H H H CSSMe Me Me A-7  H SEtH H H CSSMe Me Me A-8  H H SEt H H CSSMe Me Me A-9  H SPr^(i) H H HCSSMe Me Me A-10 H H SPr^(i) H H CSSMe Me Me A-11 H OCHF₂ H H H CSSMe MeMe A-12 Pr^(i) H NMe₂ H H CSSMe Me Me A-13 Pr^(i) NMe₂ H H H CSSMe Me MeA-14 Et Et H H H CSSMe Me Me A-15 H Et Et H H CSSMe Me Me A-16 Bu^(i) HH H H CSSMe Me Me A-17 H Bu^(i) H H H CSSMe Me Me A-18 H H Bu^(i) H HCSSMe Me Me A-19 H N(Me)Et H H H CSSMe Me Me A-20 H N(Me)Pr H H H CSSMeMe Me A-21 NPr₂ H H H H CSSMe Me Me A-22 H NPr₂ H H H CSSMe Me Me A-23 HH NPr₂ H H CSSMe Me Me A-24 H NPr₂ Me H H CSSMe Me Me A-25 H Bu^(t) H HH CSSMe Me Me

TABLE 41-B

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ A-26 H CH₂OMe H H H CSSMe Me Me A-27 H H CH₂OMeH H CSSMe Me Me A-28 CH₂OEt H H H H CSSMe Me Me A-29 H CH₂OEt H H HCSSMe Me Me A-30 H H CH₂OEt H H CSSMe Me Me A-31 CH₂SMe H H H H CSSMe MeMe A-32 H CH₂SMe H H H CSSMe Me Me A-33 H H CH₂SMe H H CSSMe Me Me A-34CH₂SEt H H H H CSSMe Me Me A-35 H CH₂SEt H H H CSSMe Me Me A-36 H HCH₂SEt H H CSSMe Me Me A-37 CH₂NMe₂ H H H H CSSMe Me Me A-38 H CH₂NMe₂ HH H CSSMe Me Me A-39 H H CH₂NMe₂ H H CSSMe Me Me A-40 CH₂NEt₂ H H H HCSSMe Me Me A-41 H CH₂NEt₂ H H H CSSMe Me Me A-42 H H CH₂NEt₂ H H CSSMeMe Me A-43 OCH₂CH₂Ome H H H H CSSMe Me Me A-44 H OCH₂CH₂OMe H H H CSSMeMe Me A-45 H H OCH₂CH₂OMe H H CSSMe Me Me A-46 OCH₂CH₂SMe H H H H CSSMeMe Me A-47 H OCH₂CH₂SMe H H H CSSMe Me Me A-48 H H OCH₂CH₂SMe H H CSSMeMe Me A-49 OCH₂CH₂NMe₂ H H H H CSSMe Me Me A-50 H OCH₂CH₂NMe₂ H H HCSSMe Me Me

TABLE 41-C

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ A-51 H H OCH₂CH₂NMe₂ H H CSSMe Me Me A-52 F H FH H CSSMe Me Me A53 Cl H Cl H H CSSMe Me Me A-54 OMe Cl H H H CSSMe MeMe A-55 OMe H Cl H H CSSMe Me Me A-56 OMe Me H H H CSSMe Me Me A-57 OMeEt H H H CSSMe Me Me A-58 OMe H Et H H CSSMe Me Me A-59 OMe H Pr^(i) H HCSSMe Me Me A-60 OMe H OEt H H CSSMe Me Me A-61 OMe H OPr H H CSSMe MeMe A-62 OMe NMe₂ H H H CSSMe Me Me A-63 OMe NEt₂ H H H CSSMe Me Me A-64OEt NMe₂ H H H CSSMe Me Me A-65 OEt NEt₂ H H H CSSMe Me Me A-66 H OMe FH H CSSMe Me Me A-67 H OMe Cl H H CSSMe Me Me A-68 H OMe OPr^(i) H HCSSMe Me Me A-69 H OEt OPr H H CSSMe Me Me A-70 H OEt OPr^(i) H H CSSMeMe Me A-71 H OEt OBu H H CSSMe Me Me A-72 SMe SMe H H H CSSMe Me Me A-73SMe H SMe H H CSSMe Me Me A-74 NMe₂ NMe₂ H H H CSSMe Me Me A-75 NMe₂ HNMe₂ H H CSSMe Me Me

TABLE 42

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-1  H H H H H COSMe Me Me B-2  Cl H H H H COSMeMe Me B-3  Br H H H H COSMe Me Me B-4  Me H H H H COSMe Me Me B-5  Et HH H H COSMe Me Me B-6  Bu H H H H COSMe Me Me B-7  Bu^(i) H H H H COSMeMe Me B-8  Bu^(t) H H H H COSMe Me Me B-9  OEt H H H H COSMe Me Me B-10OPr H H H H COSMe Me Me B-11 OCHF₂ H H H H COSMe Me Me B-12 OCF₃ H H H HCOSMe Me Me B-13 CF₃ H H H H COSMe Me Me B-14 SMe H H H H COSMe Me MeB-15 SEt H H H H COSMe Me Me B-16 SPr^(i) H H H H COSMe Me Me B-17 NMe₂H H H H COSMe Me Me B-18 NEt₂ H H H H COSMe Me Me B-19 H Cl H H H COSMeMe Me B-20 H Br H H H COSMe Me Me B-21 H Me H H H COSMe Me Me B-22 H EtH H H COSMe Me Me B-23 H Pr H H H COSMe Me Me B-24 H Bu H H H COSMe MeMe B-25 H Bu^(i) H H H COSMe Me Me

TABLE 43

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-26 H Bu^(s) H H H COSMe Me Me B-27 H Bu^(t) HH H COSMe Me Me B-28 H OMe H H H COSMe Me Me B-29 H OEt H H H COSMe MeMe B-30 H OPr H H H COSMe Me Me B-31 H OCHF₂ H H H COSMe Me Me B-32 HOCF₃ H H H COSMe Me Me B-33 H CF₃ H H H COSMe Me Me B-34 H SMe H H HCOSMe Me Me B-35 H SEt H H H COSMe Me Me B-36 H SPr^(i) H H H COSMe MeMe B-37 H NMe₂ H H H COSMe Me Me B-38 H NEt₂ H H H COSMe Me Me B-39 H HCl H H COSMe Me Me B-40 H H Br H H COSMe Me Me B-41 H H Me H H COSMe MeMe B-42 H H Pr H H COSMe Me Me B-43 H H Bu H H COSMe Me Me B-44 H HBu^(i) H H COSMe Me Me B-45 H H Bu^(s) H H COSMe Me Me B-46 H H Bu^(t) HH COSMe Me Me B-47 H H OMe H H COSMe Me Me B-48 H H OEt H H COSMe Me MeB-49 H H OPr H H COSMe Me Me B-50 H H OCHF₂ H H COSMe Me Me

TABLE 44

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ B-51 H H OCF₃ H H COSMe Me Me B-52 H H CF₃ H HCOSMe Me Me B-53 H H SMe H H COSMe Me Me B-54 H H SEt H H COSMe Me MeB-55 H H SPr^(i) H H COSMe Me Me B-56 H H NMe₂ H H COSMe Me Me B-57 H HNEt₂ H H COSMe Me Me B-58 Me Me H H H COSMe Me Me B-59 H Me Me H H COSMeMe Me B-60 Et Et H H H COSMe Me Me B-61 H Et Et H H COSMe Me Me B-62 OMeMe H H H COSMe Me Me B-63 OMe H Me H H COSMe Me Me B-64 NMe₂ Me H H HCOSMe Me Me B-65 H NMe₂ Me H H COSMe Me Me B-66 Me NMe₂ H H H COSMe MeMe B-67 NMe₂ Cl H H H COSMe Me Me B-68 Me NEt₂ H H H COSMe Me Me B-69 HNEt₂ Me H H COSMe Me Me B-70 Pr^(i) H F H H COSMe Me Me

TABLE 45

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-1  H H H H H CSSEt Me Me C-2  Cl H H H H CSSEtMe Me C-3  Br H H H H CSSEt Me Me C-4  Me H H H H CSSEt Me Me C-5  Et HH H H CSSEt Me Me C-6  Pr H H H H CSSEt Me Me C-7  Bu H H H H CSSEt MeMe C-8  Bu^(i) H H H H CSSEt Me Me C-9  Bu^(t) H H H H CSSEt Me Me C-10OMe H H H H CSSEt Me Me C-11 OPr H H H H CSSEt Me Me C-12 OCHF₂ H H H HCSSEt Me Me C-13 OCF₃ H H H H CSSEt Me Me C-14 CF₃ H H H H CSSEt Me MeC-15 SEt H H H H CSSEt Me Me C-16 SPr^(i) H H H H CSSEt Me Me C-17 NEt₂H H H H CSSEt Me Me C-18 H Cl H H H CSSEt Me Me C-19 H Br H H H CSSEt MeMe C-20 H Me H H H CSSEt Me Me C-21 H Et H H H CSSEt Me Me C-22 H Pr H HH CSSEt Me Me C-23 H Bu H H H CSSEt Me Me C-24 H Bu^(i) H H H CSSEt MeMe C-25 H Bu^(s) H H H CSSEt Me Me

TABLE 46

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-26 H Bu^(t) H H H CSSEt Me Me C-27 H OMe H H HCSSEt Me Me C-28 H OEt H H H CSSEt Me Me C-29 H OPr H H H CSSEt Me MeC-30 H OCHF₂ H H H CSSEt Me Me C-31 H OCF₃ H H H CSSEt Me Me C-32 H CF₃H H H CSSEt Me Me C-33 H SMe H H H CSSEt Me Me C-34 H SEt H H H CSSEt MeMe C-35 H SPr^(i) H H H CSSEt Me Me C-36 H NEt₂ H H H CSSEt Me Me C-37 HH Cl H H CSSEt Me Me C-38 H H Br H H CSSEt Me Me C-39 H H Me H H CSSEtMe Me C-40 H H Et H H CSSEt Me Me C-41 H H Pr H H CSSEt Me Me C-42 H HBu H H CSSEt Me Me C-43 H H Bu^(i) H H CSSEt Me Me C-44 H H Bu^(s) H HCSSEt Me Me C-45 H H Bu^(t) H H CSSEt Me Me C-46 H H OMe H H CSSEt Me MeC-47 H H OEt H H CSSEt Me Me C-48 H H OPr H H CSSEt Me Me C-49 H H OCHF₂H H CSSEt Me Me C-50 H H OCF₃ H H CSSEt Me Me

TABLE 47

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ C-51 H H CF₃ H H CSSEt Me Me C-52 H H SMe H HCSSEt Me Me C-53 H H SEt H H CSSEt Me Me C-54 H H SPr^(i) H H CSSEt MeMe C-55 H H NMe₂ H H CSSEt Me Me C-56 H H NEt₂ H H CSSEt Me Me C-57 MeMe H H H CSSEt Me Me C-58 H Me Me H H CSSEt Me Me C-59 Et Et H H H CSSEtMe Me C-60 H Et Et H H CSSEt Me Me C-61 OMe Me H H H CSSEt Me Me C-62OMe H Me H H CSSEt Me Me C-63 NMe₂ Me H H H CSSEt Me Me C-64 H NMe₂ Me HH CSSEt Me Me C-65 Me NMe₂ H H H CSSEt Me Me C-66 NMe₂ Cl H H H CSSEt MeMe C-67 Me NEt₂ H H H CSSEt Me Me C-68 H NEt₂ Me H H CSSEt Me Me C-69Pr^(i) H F H H CSSEt Me Me C-70 OMe H OMe H H CSSEt Me Me C-71 H OMe OMeH H CSSEt Me Me C-72 H OMe OEt H H CSSEt Me Me C-73 H OEt OMe H H CSSEtMe Me C-74 H OEt OEt H H CSSEt Me Me C-75 OMe H Me H H CSSEt Me Me

TABLE 48

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ D-1  Br H H H H COSEt Me Me D-2  Bu^(i) H H H HCOSEt Me Me D-3  OPr H H H H COSEt Me Me D-4  OCHF₂ H H H H COSEt Me MeD-5  OCF₃ H H H H COSEt Me Me D-6  NEt₂ H H H H COSEt Me Me D-7  H Cl HH H COSEt Me Me D-8  H Br H H H COSEt Me Me D-9  H Et H H H COSEt Me MeD-10 H Pr H H H COSEt Me Me D-11 H Bu H H H COSEt Me Me D-12 H Bu^(i) HH H COSEt Me Me D-13 H Bu^(s) H H H COSEt Me Me D-14 H Bu^(t) H H HCOSEt Me Me D-15 H OEt H H H COSEt Me Me D-16 H OPr H H H COSEt Me MeD-17 H OCHF₂ H H H COSEt Me Me D-18 H OCF₃ H H H COSEt Me Me D-19 H CF₃H H H COSEt Me Me D-20 H SMe H H H COSEt Me Me D-21 H SEt H H H COSEt MeMe D-22 H SPr^(i) H H H COSEt Me Me D-23 H NMe₂ H H H COSEt Me Me D-24 HNEt₂ H H H COSEt Me Me D-25 H H Br H H COSEt Me Me

TABLE 49

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ D-26 H H Et H H COSEt Me Me D-27 H H Pr H HCOSEt Me Me D-28 H H Bu H H COSEt Me Me D-29 H H Bu^(i) H H COSEt Me MeD-30 H H Bu^(s) H H COSEt Me Me D-31 H H Bu^(t) H H COSEt Me Me D-32 H HOMe H H COSEt Me Me D-33 H H OEt H H COSEt Me Me D-34 H H OPr H H COSEtMe Me D-35 H H OCHF₂ H H COSEt Me Me D-36 H H OCF₃ H H COSEt Me Me D-37H H CF₃ H H COSEt Me Me D-38 H H SMe H H COSEt Me Me D-39 H H SEt H HCOSEt Me Me D-40 H H SPr^(i) H H COSEt Me Me D-41 H H NMe₂ H H COSEt MeMe D-42 H H NEt₂ H H COSEt Me Me D-43 Et Et H H H COSEt Me Me D-44 H EtEt H H COSEt Me Me D-45 OMe Me H H H COSEt Me Me D-46 OMe H Me H H COSEtMe Me D-47 NMe₂ Me H H H COSEt Me Me D-48 H NMe₂ Me H H COSEt Me Me D-49H OEt OMe H H COSEt Me Me D-50 H OEt OEt H H COSEt Me Me

TABLE 50

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-1  H H H H H CSSMe Et Et E-2  Cl H H H H CSSMeEt Et E-3  Br H H H H CSSMe Et Et E-4  Me H H H H CSSMe Et Et E-5  Et HH H H CSSMe Et Et E-6  Pr H H H H CSSMe Et Et E-7  Bu H H H H CSSMe EtEt E-8  Bu^(i) H H H H CSSMe Et Et E-9  Bu^(t) H H H H CSSMe Et Et E-10OMe H H H H CSSMe Et Et E-11 OEt H H H H CSSMe Et Et E-12 OPr^(i) H H HH CSSMe Et Et E-13 OPr H H H H CSSMe Et Et E-14 OCHF₂ H H H H CSSMe EtEt E-15 OCF₃ H H H H CSSMe Et Et E-16 CF₃ H H H H CSSMe Et Et E-17 SMe HH H H CSSMe Et Et E-18 SEt H H H H CSSMe Et Et E-19 SPr^(i) H H H HCSSMe Et Et E-20 NMe₂ H H H H CSSMe Et Et E-21 NEt₂ H H H H CSSMe Et EtE-22 H Cl H H H CSSMe Et Et E-23 H Br H H H CSSMe Et Et E-24 H Me H H HCSSMe Et Et E-25 H Et H H H CSSMe Et Et

TABLE 51

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-26 H Pr H H H CSSMe Et Et E-27 H Pr^(i) H H HCSSMe Et Et E-28 H Bu H H H CSSMe Et Et E-29 H Bu^(i) H H H CSSMe Et EtE-30 H Bu^(s) H H H CSSMe Et Et E-31 H Bu^(t) H H H CSSMe Et Et E-32 HOMe H H H CSSMe Et Et E-33 H OEt H H H CSSMe Et Et E-34 H OPr H H HCSSMe Et Et E-35 H OPr^(i) H H H CSSMe Et Et E-36 H OCHF₂ H H H CSSMe EtEt E-37 H OCF₃ H H H CSSMe Et Et E-38 H CF₃ H H H CSSMe Et Et E-39 H SMeH H H CSSMe Et Et E-40 H SEt H H H CSSMe Et Et E-41 H SPr^(i) H H HCSSMe Et Et E-42 H NMe₂ H H H CSSMe Et Et E-43 H NEt₂ H H H CSSMe Et EtE-44 H H Cl H H CSSMe Et Et E-45 H H Br H H CSSMe Et Et E-46 H H Me H HCSSMe Et Et E-47 H H Et H H CSSMe Et Et E-48 H H Pr H H CSSMe Et Et E-49H H Pr^(i) H H CSSMe Et Et E-50 H H Bu H H CSSMe Et Et

TABLE 52

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ E-51 H H Bu^(i) H H CSSMe Et Et E-52 H H Bu^(s)H H CSSMe Et Et E-53 H H Bu^(t) H H CSSMe Et Et E-54 H H OMe H H CSSMeEt Et E-55 H H OEt H H CSSMe Et Et E-56 H H OPr H H CSSMe Et Et E-57 H HOPr^(i) H H CSSMe Et Et E-58 H H OCHF₂ H H CSSMe Et Et E-59 H H OCF₃ H HCSSMe Et Et E-60 H H CF₃ H H CSSMe Et Et E-61 H H SMe H H CSSMe Et EtE-62 H H SEt H H CSSMe Et Et E-63 H H SPr^(i) H H CSSMe Et Et E-64 H HNMe₂ H H CSSMe Et Et E-65 H H NEt₂ H H CSSMe Et Et E-66 Me NMe₂ H H HCSSMe Et Et E-67 NMe₂ Cl H H H CSSMe Et Et E-68 Me NEt₂ H H H CSSMe EtEt E-69 H NEt₂ Me H H CSSMe Et Et E-70 Pr^(i) H F H H CSSMe Et Et E-71OMe H OMe H H CSSMe Et Et E-72 H OMe OMe H H CSSMe Et Et E-73 H OMe OEtH H CSSMe Et Et E-74 H OEt OMe H H CSSMe Et Et E-75 H OEt OEt H H CSSMeEt Et

TABLE 53

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-1  H H H H H CSSMe Pr Pr F-2  Cl H H H H CSSMePr Pr F-3  Br H H H H CSSMe Pr Pr F-4  Me H H H H CSSMe Pr Pr F-5  Et HH H H CSSMe Pr Pr F-6  Pr H H H H CSSMe Pr Pr F-7  Bu H H H H CSSMe PrPr F-8  Bu^(i) H H H H CSSMe Pr Pr F-9  Bu^(t) H H H H CSSMe Pr Pr F-10OMe H H H H CSSMe Pr Pr F-11 OEt H H H H CSSMe Pr Pr F-12 OPr^(i) H H HH CSSMe Pr Pr F-13 OPr H H H H CSSMe Pr Pr F-14 OCHF₂ H H H H CSSMe PrPr F-15 OCF₃ H H H H CSSMe Pr Pr F-16 CF₃ H H H H CSSMe Pr Pr F-17 SMe HH H H CSSMe Pr Pr F-18 SEt H H H H CSSMe Pr Pr F-19 SPr^(i) H H H HCSSMe Pr Pr F-20 NMe₂ H H H H CSSMe Pr Pr F-21 NEt₂ H H H H CSSMe Pr PrF-22 H Cl H H H CSSMe Pr Pr F-23 H Br H H H CSSMe Pr Pr F-24 H Me H H HCSSMe Pr Pr F-25 H Et H H H CSSMe Pr Pr

TABLE 54

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-26 H Pr H H H CSSMe Pr Pr F-27 H Pr^(i) H H HCSSMe Pr Pr F-28 H Bu H H H CSSMe Pr Pr F-29 H Bu^(i) H H H CSSMe Pr PrF-30 H Bu^(s) H H H CSSMe Pr Pr F-31 H Bu^(t) H H H CSSMe Pr Pr F-32 HOMe H H H CSSMe Pr Pr F-33 H OEt H H H CSSMe Pr Pr F-34 H OPr H H HCSSMe Pr Pr F-35 H OPr^(i) H H H CSSMe Pr Pr F-36 H OCHF₂ H H H CSSMe PrPr F-37 H OCF₃ H H H CSSMe Pr Pr F-38 H CF₃ H H H CSSMe Pr Pr F-39 H SMeH H H CSSMe Pr Pr F-40 H SEt H H H CSSMe Pr Pr F-41 H SPr^(i) H H HCSSMe Pr Pr F-42 H NMe₂ H H H CSSMe Pr Pr F-43 H NEt₂ H H H CSSMe Pr PrF-44 H H Cl H H CSSMe Pr Pr F-45 H H Br H H CSSMe Pr Pr F-46 H H Me H HCSSMe Pr Pr F-47 H H Et H H CSSMe Pr Pr F-48 H H Pr H H CSSMe Pr Pr F-49H H Pr^(i) H H CSSMe Pr Pr F-50 H H Bu H H CSSMe Pr Pr

TABLE 55

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ F-51 H H Bu^(i) H H CSSMe Pr Pr F-52 H H Bu^(s)H H CSSMe Pr Pr F-53 H H Bu^(t) H H CSSMe Pr Pr F-54 H H OMe H H CSSMePr Pr F-55 H H OEt H H CSSMe Pr Pr F-56 H H OPr H H CSSMe Pr Pr F-57 H HOPr^(i) H H CSSMe Pr Pr F-58 H H OCHF₂ H H CSSMe Pr Pr F-59 H H OCF₃ H HCSSMe Pr Pr F-60 H H CF₃ H H CSSMe Pr Pr F-61 H H SMe H H CSSMe Pr PrF-62 H H SEt H H CSSMe Pr Pr F-63 H H SPr^(i) H H CSSMe Pr Pr F-64 H HNMe₂ H H CSSMe Pr Pr F-65 H H NEt₂ H H CSSMe Pr Pr F-66 Me NMe₂ H H HCSSMe Pr Pr F-67 NMe₂ Cl H H H CSSMe Pr Pr F-68 Me NEt₂ H H H CSSMe PrPr F-69 H NEt₂ Me H H CSSMe Pr Pr F-70 Bu^(s) H H H H CSSMe Pr Pr F-71OMe H OMe H H CSSMe Pr Pr F-72 H OMe OMe H H CSSMe Pr Pr F-73 H OMe OEtH H CSSMe Pr Pr F-74 H OEt OMe H H CSSMe Pr Pr F-75 H OEt OEt H H CSSMePr Pr

TABLE 56

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-1  H H H H H CSSEt Et Et G-2  Cl H H H H CSSEtEt Et G-3  Br H H H H CSSEt Et Et G-4  Me H H H H CSSEt Et Et G-5  Et HH H H CSSEt Et Et G-6  Pr H H H H CSSEt Et Et G-7  Bu H H H H CSSEt EtEt G-8  Bu^(i) H H H H CSSEt Et Et G-9  Bu^(t) H H H H CSSEt Et Et G-10OMe H H H H CSSEt Et Et G-11 OEt H H H H CSSEt Et Et G-12 OPr^(i) H H HH CSSEt Et Et G-13 OPr H H H H CSSEt Et Et G-14 OCHF₂ H H H H CSSEt EtEt G-15 OCF₃ H H H H CSSEt Et Et G-16 CF₃ H H H H CSSEt Et Et G-17 SMe HH H H CSSEt Et Et G-18 SEt H H H H CSSEt Et Et G-19 SPr^(i) H H H HCSSEt Et Et G-20 NMe₂ H H H H CSSEt Et Et G-21 NEt₂ H H H H CSSEt Et EtG-22 H Cl H H H CSSEt Et Et G-23 H Br H H H CSSEt Et Et G-24 H Me H H HCSSEt Et Et G-25 H Et H H H CSSEt Et Et

TABLE 57

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-26 H Pr H H H CSSEt Et Et G-27 H Pr^(i) H H HCSSEt Et Et G-28 H Bu H H H CSSEt Et Et G-29 H Bu^(i) H H H CSSEt Et EtG-30 H Bu^(s) H H H CSSEt Et Et G-31 H Bu^(t) H H H CSSEt Et Et G-32 HOMe H H H CSSEt Et Et G-33 H OEt H H H CSSEt Et Et G-34 H OPr H H HCSSEt Et Et G-35 H OPr^(i) H H H CSSEt Et Et G-36 H OCHF₂ H H H CSSEt EtEt G-37 H OCF₃ H H H CSSEt Et Et G-38 H CF₃ H H H CSSEt Et Et G-39 H SMeH H H CSSEt Et Et G-40 H SEt H H H CSSEt Et Et G-41 H SPr^(i) H H HCSSEt Et Et G-42 H NMe₂ H H H CSSEt Et Et G-43 H NEt₂ H H H CSSEt Et EtG-44 H H Cl H H CSSEt Et Et G-45 H H Br H H CSSEt Et Et G-46 H H Me H HCSSEt Et Et G-47 H H Et H H CSSEt Et Et G-48 H H Pr H H CSSEt Et Et G-49H H Pr^(i) H H CSSEt Et Et G-50 H H Bu H H CSSEt Et Et

TABLE 58

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ G-51 H H Bu^(i) H H CSSEt Et Et G-52 H H Bu^(s)H H CSSEt Et Et G-53 H H Bu^(t) H H CSSEt Et Et G-54 H H OMe H H CSSEtEt Et G-55 H H OEt H H CSSEt Et Et G-56 H H OPr H H CSSEt Et Et G-57 H HOPr^(i) H H CSSEt Et Et G-58 H H OCHF₂ H H CSSEt Et Et G-59 H H OCF₃ H HCSSEt Et Et G-60 H H CF₃ H H CSSEt Et Et G-61 H H SMe H H CSSEt Et EtG-62 H H SEt H H CSSEt Et Et G-63 H H SPr^(i) H H CSSEt Et Et G-64 H HNMe₂ H H CSSEt Et Et G-65 H H NEt₂ H H CSSEt Et Et G-66 Me NMe₂ H H HCSSEt Et Et G-67 NMe₂ Cl H H H CSSEt Et Et G-68 Me NEt₂ H H H CSSEt EtEt G-69 H NEt₂ Me H H CSSEt Et Et G-70 Bu^(s) H H H H CSSEt Et Et G-71OMe H OMe H H CSSEt Et Et G-72 H OMe OMe H H CSSEt Et Et G-73 H OMe OEtH H CSSEt Et Et G-74 H OEt OMe H H CSSEt Et Et G-75 H OEt OEt H H CSSEtEt Et

TABLE 59

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ H-1  H H H H H CSSMe —(CH₂)₂— H-2  Cl H H H HCSSMe —(CH₂)₂— H-3  Br H H H H CSSMe —(CH₂)₂— H-4  Me H H H H CSSMe—(CH₂)₂— H-5  Et H H H H CSSMe —(CH₂)₂— H-6  Pr H H H H CSSMe —(CH₂)₂—H-7  Bu H H H H CSSMe —(CH₂)₂— H-8  Bu^(i) H H H H CSSMe —(CH₂)₂— H-9 Bu^(t) H H H H CSSMe —(CH₂)₂— H-10 OMe H H H H CSSMe —(CH₂)₂— H-11 OEt HH H H CSSMe —(CH₂)₂— H-12 OPr^(i) H H H H CSSMe —(CH₂)₂— H-13 OPr H H HH CSSMe —(CH₂)₂— H-14 OCHF₂ H H H H CSSMe —(CH₂)₂— H-15 OCF₃ H H H HCSSMe —(CH₂)₂— H-16 CF₃ H H H H CSSMe —(CH₂)₂— H-17 SMe H H H H CSSMe—(CH₂)₂— H-18 SEt H H H H CSSMe —(CH₂)₂— H-19 SPr^(i) H H H H CSSMe—(CH₂)₂— H-20 NMe₂ H H H H CSSMe —(CH₂)₂— H-21 NEt₂ H H H H CSSMe—(CH₂)₂— H-22 H Cl H H H CSSMe —(CH₂)₂— H-23 H Br H H H CSSMe —(CH₂)₂—H-24 H Me H H H CSSMe —(CH₂)₂— H-25 H Et H H H CSSMe —(CH₂)₂—

TABLE 60

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ H-26 H Pr H H H CSSMe —(CH₂)₂— H-27 H Pr^(i) H HH CSSMe —(CH₂)₂— H-28 H Bu H H H CSSMe —(CH₂)₂— H-29 H Bu^(i) H H HCSSMe —(CH₂)₂— H-30 H Bu^(s) H H H CSSMe —(CH₂)₂— H-31 H Bu^(t) H H HCSSMe —(CH₂)₂— H-32 H OMe H H H CSSMe —(CH₂)₂— H-33 H OEt H H H CSSMe—(CH₂)₂— H-34 H OPr H H H CSSMe —(CH₂)₂— H-35 H OPr^(i) H H H CSSMe—(CH₂)₂— H-36 H OCHF₂ H H H CSSMe —(CH₂)₂— H-37 H OCF₃ H H H CSSMe—(CH₂)₂— H-38 H CF₃ H H H CSSMe —(CH₂)₂— H-39 H SMe H H H CSSMe —(CH₂)₂—H-40 H SEt H H H CSSMe —(CH₂)₂— H-41 H SPr^(i) H H H CSSMe —(CH₂)₂— H-42H NMe₂ H H H CSSMe —(CH₂)₂— H-43 H NEt₂ H H H CSSMe —(CH₂)₂— H-44 H H ClH H CSSMe —(CH₂)₂— H-45 H H Br H H CSSMe —(CH₂)₂— H-46 H H Me H H CSSMe—(CH₂)₂— H-47 H H Et H H CSSMe —(CH₂)₂— H-48 H H Pr H H CSSMe —(CH₂)₂—H-49 H H Pr^(i) H H CSSMe —(CH₂)₂— H-50 H H Bu H H CSSMe —(CH₂)₂—

TABLE 61

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ H-51 H H Bu^(i) H H CSSMe —(CH₂)₂— H-52 H HBu^(s) H H CSSMe —(CH₂)₂— H-53 H H Bu^(t) H H CSSMe —(CH₂)₂— H-54 H HOMe H H CSSMe —(CH₂)₂— H-55 H H OEt H H CSSMe —(CH₂)₂— H-56 H H OPr H HCSSMe —(CH₂)₂— H-57 H H OPr^(i) H H CSSMe —(CH₂)₂— H-58 H H OCHF₂ H HCSSMe —(CH₂)₂— H-59 H H OCF₃ H H CSSMe —(CH₂)₂— H-60 H H CF₃ H H CSSMe—(CH₂)₂— H-61 H H SMe H H CSSMe —(CH₂)₂— H-62 H H SEt H H CSSMe —(CH₂)₂—H-63 H H SPr^(i) H H CSSMe —(CH₂)₂— H-64 H H NMe₂ H H CSSMe —(CH₂)₂—H-65 H H NEt₂ H H CSSMe —(CH₂)₂— H-66 Me NMe₂ H H H CSSMe —(CH₂)₂— H-67NMe₂ Cl H H H CSSMe —(CH₂)₂— H-68 Me NEt₂ H H H CSSMe —(CH₂)₂— H-69 HNEt₂ Me H H CSSMe —(CH₂)₂— H-70 Bu^(s) H H H H CSSMe —(CH₂)₂— H-71 OMe HOMe H H CSSMe —(CH₂)₂— H-72 H OMe OMe H H CSSMe —(CH₂)₂— H-73 H OMe OEtH H CSSMe —(CH₂)₂— H-74 H OEt OMe H H CSSMe —(CH₂)₂— H-75 H OEt OEt H HCSSMe —(CH₂)₂—

TABLE 62

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-1  H H H H H CSSMe —(CH₂)₄— N-2  Cl H H H HCSSMe —(CH₂)₄— N-3  Br H H H H CSSMe —(CH₂)₄— N-4  Me H H H H CSSMe—(CH₂)₄— N-5  Et H H H H CSSMe —(CH₂)₄— N-6  Pr H H H H CSSMe —(CH₂)₄—N-7  Bu H H H H CSSMe —(CH₂)₄— N-8  Bu^(i) H H H H CSSMe —(CH₂)₄— N-9 Bu^(t) H H H H CSSMe —(CH₂)₄— N-10 OMe H H H H CSSMe —(CH₂)₄— N-11 OEt HH H H CSSMe —(CH₂)₄— N-12 OPr^(i) H H H H CSSMe —(CH₂)₄— N-13 OPr H H HH CSSMe —(CH₂)₄— N-14 OCHF₂ H H H H CSSMe —(CH₂)₄— N-15 OCF₃ H H H HCSSMe —(CH₂)₄— N-16 CF₃ H H H H CSSMe —(CH₂)₄— N-17 SMe H H H H CSSMe—(CH₂)₄— N-18 SEt H H H H CSSMe —(CH₂)₄— N-19 SPr^(i) H H H H CSSMe—(CH₂)₄— N-20 NMe₂ H H H H CSSMe —(CH₂)₄— N-21 NEt₂ H H H H CSSMe—(CH₂)₄— N-22 H Cl H H H CSSMe —(CH₂)₄— N-23 H Br H H H CSSMe —(CH₂)₄—N-24 H Me H H H CSSMe —(CH₂)₄— N-25 H Et H H H CSSMe —(CH₂)₄—

TABLE 63

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-26 H Pr H H H CSSMe —(CH₂)₄— N-27 H Pr^(i) H HH CSSMe —(CH₂)₄— N-28 H Bu H H H CSSMe —(CH₂)₄— N-29 H Bu^(i) H H HCSSMe —(CH₂)₄— N-30 H Bu^(s) H H H CSSMe —(CH₂)₄— N-31 H Bu^(t) H H HCSSMe —(CH₂)₄— N-32 H OMe H H H CSSMe —(CH₂)₄— N-33 H OEt H H H CSSMe—(CH₂)₄— N-34 H OPr H H H CSSMe —(CH₂)₄— N-35 H OPr^(i) H H H CSSMe—(CH₂)₄— N-36 H OCHF₂ H H H CSSMe —(CH₂)₄— N-37 H OCF₃ H H H CSSMe—(CH₂)₄— N-38 H CF₃ H H H CSSMe —(CH₂)₄— N-39 H SMe H H H CSSMe —(CH₂)₄—N-40 H SEt H H H CSSMe —(CH₂)₄— N-41 H SPr^(i) H H H CSSMe —(CH₂)₄— N-42H NMe₂ H H H CSSMe —(CH₂)₄— N-43 H NEt₂ H H H CSSMe —(CH₂)₄— N-44 H H ClH H CSSMe —(CH₂)₄— N-45 H H Br H H CSSMe —(CH₂)₄— N-46 H H Me H H CSSMe—(CH₂)₄— N-47 H H Et H H CSSMe —(CH₂)₄— N-48 H H Pr H H CSSMe —(CH₂)₄—N-49 H H Pr^(i) H H CSSMe —(CH₂)₄— N-50 H H Bu H H CSSMe —(CH₂)₄—

TABLE 64

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ N-51 H H Bu^(i) H H CSSMe —(CH₂)₄— N-52 H HBu^(s) H H CSSMe —(CH₂)₄— N-53 H H Bu^(t) H H CSSMe —(CH₂)₄— N-54 H HOMe H H CSSMe —(CH₂)₄— N-55 H H OEt H H CSSMe —(CH₂)₄— N-56 H H OPr H HCSSMe —(CH₂)₄— N-57 H H OPr^(i) H H CSSMe —(CH₂)₄— N-58 H H OCHF₂ H HCSSMe —(CH₂)₄— N-59 H H OCF₃ H H CSSMe —(CH₂)₄— N-60 H H CF₃ H H CSSMe—(CH₂)₄— N-61 H H SMe H H CSSMe —(CH₂)₄— N-62 H H SEt H H CSSMe —(CH₂)₄—N-63 H H SPr^(i) H H CSSMe —(CH₂)₄— N-64 H H NMe₂ H H CSSMe —(CH₂)₄—N-65 H H NEt₂ H H CSSMe —(CH₂)₄— N-66 Me NMe₂ H H H CSSMe —(CH₂)₄— N-67NMe₂ Cl H H H CSSMe —(CH₂)₄— N-68 Me NEt₂ H H H CSSMe —(CH₂)₄— N-69 HNEt₂ Me H H CSSMe —(CH₂)₄— N-70 Bu^(s) H H H H CSSMe —(CH₂)₄— N-71 OMe HOMe H H CSSMe —(CH₂)₄— N-72 H OMe OMe H H CSSMe —(CH₂)₄— N-73 H OMe OEtH H CSSMe —(CH₂)₄— N-74 H OEt OMe H H CSSMe —(CH₂)₄— N-75 H OEt OEt H HCSSMe —(CH₂)₄—

TABLE 65

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-1  H H H H H CSSMe —(CH₂)₅— J-2  Cl H H H HCSSMe —(CH₂)₅— J-3  Br H H H H CSSMe —(CH₂)₅— J-4  Me H H H H CSSMe—(CH₂)₅— J-5  Et H H H H CSSMe —(CH₂)₅— J-6  Pr H H H H CSSMe —(CH₂)₅—J-7  Bu H H H H CSSMe —(CH₂)₅— J-8  Bu^(i) H H H H CSSMe —(CH₂)₅— J-9 Bu^(t) H H H H CSSMe —(CH₂)₅— J-10 OMe H H H H CSSMe —(CH₂)₅— J-11 OEt HH H H CSSMe —(CH₂)₅— J-12 OPr^(i) H H H H CSSMe —(CH₂)₅— J-13 OPr H H HH CSSMe —(CH₂)₅— J-14 OCHF₂ H H H H CSSMe —(CH₂)₅— J-15 OCF₃ H H H HCSSMe —(CH₂)₅— J-16 CF₃ H H H H CSSMe —(CH₂)₅— J-17 SMe H H H H CSSMe—(CH₂)₅— J-18 SEt H H H H CSSMe —(CH₂)₅— J-19 SPr^(i) H H H H CSSMe—(CH₂)₅— J-20 NMe₂ H H H H CSSMe —(CH₂)₅— J-21 NEt₂ H H H H CSSMe—(CH₂)₅— J-22 H Cl H H H CSSMe —(CH₂)₅— J-23 H Br H H H CSSMe —(CH₂)₅—J-24 H Me H H H CSSMe —(CH₂)₅— J-25 H Et H H H CSSMe —(CH₂)₅—

TABLE 66

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-26 H Pr H H H CSSMe —(CH₂)₅— J-27 H Pr^(i) H HH CSSMe —(CH₂)₅— J-28 H Bu H H H CSSMe —(CH₂)₅— J-29 H Bu^(i) H H HCSSMe —(CH₂)₅— J-30 H Bu^(s) H H H CSSMe —(CH₂)₅— J-31 H Bu^(t) H H HCSSMe —(CH₂)₅— J-32 H OMe H H H CSSMe —(CH₂)₅— J-33 H OEt H H H CSSMe—(CH₂)₅— J-34 H OPr H H H CSSMe —(CH₂)₅— J-35 H OPr^(i) H H H CSSMe—(CH₂)₅— J-36 H OCHF₂ H H H CSSMe —(CH₂)₅— J-37 H OCF₃ H H H CSSMe—(CH₂)₅— J-38 H CF₃ H H H CSSMe —(CH₂)₅— J-39 H SMe H H H CSSMe —(CH₂)₅—J-40 H SEt H H H CSSMe —(CH₂)₅— J-41 H SPr^(i) H H H CSSMe —(CH₂)₅— J-42H NMe₂ H H H CSSMe —(CH₂)₅— J-43 H NEt₂ H H H CSSMe —(CH₂)₅— J-44 H H ClH H CSSMe —(CH₂)₅— J-45 H H Br H H CSSMe —(CH₂)₅— J-46 H H Me H H CSSMe—(CH₂)₅— J-47 H H Et H H CSSMe —(CH₂)₅— J-48 H H Pr H H CSSMe —(CH₂)₅—J-49 H H Pr^(i) H H CSSMe —(CH₂)₅— J-50 H H Bu H H CSSMe —(CH₂)₅—

TABLE 67

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ J-51 H H Bu^(i) H H CSSMe —(CH₂)₅— J-52 H HBu^(s) H H CSSMe —(CH₂)₅— J-53 H H Bu^(t) H H CSSMe —(CH₂)₅— J-54 H HOMe H H CSSMe —(CH₂)₅— J-55 H H OEt H H CSSMe —(CH₂)₅— J-56 H H OPr H HCSSMe —(CH₂)₅— J-57 H H OPr^(i) H H CSSMe —(CH₂)₅— J-58 H H OCHF₂ H HCSSMe —(CH₂)₅— J-59 H H OCF₃ H H CSSMe —(CH₂)₅— J-60 H H CF₃ H H CSSMe—(CH₂)₅— J-61 H H SMe H H CSSMe —(CH₂)₅— J-62 H H SEt H H CSSMe —(CH₂)₅—J-63 H H SPr^(i) H H CSSMe —(CH₂)₅— J-64 H H NMe₂ H H CSSMe —(CH₂)₅—J-65 H H NEt₂ H H CSSMe —(CH₂)₅— J-66 Me NMe₂ H H H CSSMe —(CH₂)₅— J-67NMe₂ Cl H H H CSSMe —(CH₂)₅— J-68 Me NEt₂ H H H CSSMe —(CH₂)₅— J-69 HNEt₂ Me H H CSSMe —(CH₂)₅— J-70 Bu^(s) H H H H CSSMe —(CH₂)₅— J-71 OMe HOMe H H CSSMe —(CH₂)₅— J-72 H OMe OMe H H CSSMe —(CH₂)₅— J-73 H OMe OEtH H CSSMe —(CH₂)₅— J-74 H OEt OMe H H CSSMe —(CH₂)₅— J-75 H OEt OEt H HCSSMe —(CH₂)₅—

TABLE 68

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-1  H H H H H COSEt Et Et K-2  Cl H H H H COSEtEt Et K-3  Br H H H H COSEt Et Et K-4  Me H H H H COSEt Et Et K-5  Et HH H H COSEt Et Et K-6  Pr H H H H COSEt Et Et K-7  Bu H H H H COSEt EtEt K-8  Bu^(i) H H H H COSEt Et Et K-9  Bu^(t) H H H H COSEt Et Et K-10OMe H H H H COSEt Et Et K-11 OEt H H H H COSEt Et Et K-12 OPr^(i) H H HH COSEt Et Et K-13 OPr H H H H COSEt Et Et K-14 OCHF₂ H H H H COSEt EtEt K-15 OCF₃ H H H H COSEt Et Et K-16 CF₃ H H H H COSEt Et Et K-17 SMe HH H H COSEt Et Et K-18 SEt H H H H COSEt Et Et K-19 SPr^(i) H H H HCOSEt Et Et K-20 NMe₂ H H H H COSEt Et Et K-21 NEt₂ H H H H COSEt Et EtK-22 H Cl H H H COSEt Et Et K-23 H Br H H H COSEt Et Et K-24 H Me H H HCOSEt Et Et K-25 H Et H H H COSEt Et Et

TABLE 69

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-26 H Pr H H H COSEt Et Et K-27 H Pr^(i) H H HCOSEt Et Et K-28 H Bu H H H COSEt Et Et K-29 H Bu^(i) H H H COSEt Et EtK-30 H Bu^(s) H H H COSEt Et Et K-31 H Bu^(t) H H H COSEt Et Et K-32 HOMe H H H COSEt Et Et K-33 H OEt H H H COSEt Et Et K-34 H OPr H H HCOSEt Et Et K-35 H OPr^(i) H H H COSEt Et Et K-36 H OCHF₂ H H H COSEt EtEt K-37 H OCF₃ H H H COSEt Et Et K-38 H CF₃ H H H COSEt Et Et K-39 H SMeH H H COSEt Et Et K-40 H SEt H H H COSEt Et Et K-41 H SPr^(i) H H HCOSEt Et Et K-42 H NMe₂ H H H COSEt Et Et K-43 H NEt₂ H H H COSEt Et EtK-44 H H Cl H H COSEt Et Et K-45 H H Br H H COSEt Et Et K-46 H H Me H HCOSEt Et Et K-47 H H Et H H COSEt Et Et K-48 H H Pr H H COSEt Et Et K-49H H Pr^(i) H H COSEt Et Et K-50 H H Bu H H COSEt Et Et

TABLE 70

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ K-51 H H Bu^(i) H H COSEt Et Et K-52 H H Bu^(s)H H COSEt Et Et K-53 H H Bu^(t) H H COSEt Et Et K-54 H H OMe H H COSEtEt Et K-55 H H OEt H H COSEt Et Et K-56 H H OPr H H COSEt Et Et K-57 H HOPr^(i) H H COSEt Et Et K-58 H H OCHF₂ H H COSEt Et Et K-59 H H OCF₃ H HCOSEt Et Et K-60 H H CF₃ H H COSEt Et Et K-61 H H SMe H H COSEt Et EtK-62 H H SEt H H COSEt Et Et K-63 H H SPr^(i) H H COSEt Et Et K-64 H HNMe₂ H H COSEt Et Et K-65 H H NEt₂ H H COSEt Et Et K-66 Me NMe₂ H H HCOSEt Et Et K-67 NMe₂ Cl H H H COSEt Et Et K-68 Me NEt₂ H H H COSEt EtEt K-69 H NEt₂ Me H H COSEt Et Et K-70 Bu^(s) H H H H COSEt Et Et K-71OMe H OMe H H COSEt Et Et K-72 H OMe OMe H H COSEt Et Et K-73 H OMe OEtH H COSEt Et Et K-74 H OEt OMe H H COSEt Et Et K-75 H OEt OEt H H COSEtEt Et

TABLE 71

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-1  H H H H H COSMe Et Et L-2  Cl H H H H COSMeEt Et L-3  Br H H H H COSMe Et Et L-4  Me H H H H COSMe Et Et L-5  Et HH H H COSMe Et Et L-6  Pr H H H H COSMe Et Et L-7  Bu H H H H COSMe EtEt L-8  Bu^(i) H H H H COSMe Et Et L-9  Bu^(t) H H H H COSMe Et El L-10OMe H H H H COSMe Et Et L-11 OEt H H H H COSMe Et Et L-12 OPr^(i) H H HH COSMe Et Et L-13 OPr H H H H COSMe Et Et L-14 OCHF₂ H H H H COSMe EtEt L-15 OCF₃ H H H H COSMe Et Et L-16 CF₃ H H H H COSMe Et Et L-17 SMe HH H H COSMe Et Et L-18 SEt H H H H COSMe Et Et L-19 SPr^(i) H H H HCOSMe Et Et L-20 NMe₂ H H H H COSMe Et Et L-21 NEt₂ H H H H COSMe Et EtL-22 H Cl H H H COSMe Et Et L-23 H Br H H H COSMe Et Et L-24 H Me H H HCOSMe Et Et L-25 H Et H H H COSMe Et Et

TABLE 72

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-26 H Pr H H H COSMe Et Et L-27 H Pr^(i) H H HCOSMe Et Et L-28 H Bu H H H COSMe Et Et L-29 H Bu^(i) H H H COSMe Et EtL-30 H Bu^(s) H H H COSMe Et Et L-31 H Bu^(t) H H H COSMe Et Et L-32 HOMe H H H COSMe Et Et L-33 H OEt H H H COSMe Et Et L-34 H OPr H H HCOSMe Et Et L-35 H OPr^(i) H H H COSMe Et Et L-36 H OCHF₂ H H H COSMe EtEt L-37 H OCF₃ H H H COSMe Et Et L-38 H CF₃ H H H COSMe Et Et L-39 H SMeH H H COSMe Et Et L-40 H SEt H H H COSMe Et Et L-41 H SPr^(i) H H HCOSMe Et Et L-42 H NMe₂ H H H COSMe Et Et L-43 H NEt₂ H H H COSMe Et EtL-44 H H Cl H H COSMe Et Et L-45 H H Br H H COSMe Et Et L-46 H H Me H HCOSMe Et Et L-47 H H Et H H COSMe Et Et L-48 H H Pr H H COSMe Et Et L-49H H Pr^(i) H H COSMe Et Et L-50 H H Bu H H COSMe Et Et

TABLE 73

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ L-51 H H Bu^(i) H H COSMe Et Et L-52 H H Bu^(s)H H COSMe Et Et L-53 H H Bu^(t) H H COSMe Et Et L-54 H H OMe H H COSMeEt Et L-55 H H OEt H H COSMe Et Et L-56 H H OPr H H COSMe Et Et L-57 H HOPr^(i) H H COSMe Et Et L-58 H H OCHF₂ H H COSMe Et Et L-59 H H OCF₃ H HCOSMe Et Et L-60 H H CF₃ H H COSMe Et Et L-61 H H SMe H H COSMe Et EtL-62 H H SEt H H COSMe Et Et L-63 H H SPr^(i) H H COSMe Et Et L-64 H HNMe₂ H H COSMe Et Et L-65 H H NEt₂ H H COSMe Et Et L-66 Me NMe₂ H H HCOSMe Et Et L-67 NMe₂ Cl H H H COSMe Et Et L-68 Me NEt₂ H H H COSMe EtEt L-69 H NEt₂ Me H H COSMe Et Et L-70 Bu^(s) H H H H COSMe Et Et L-71Pr^(i) H H H H COSMe Et Et L-72 H OMe OMe H H COSMe Et Et L-73 H OMe OEtH H COSMe Et Et L-74 H OEt OMe H H COSMe Et Et L-75 H OEt OEt H H COSMeEt Et

TABLE 74

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-1  H H H H H COSMe —(CH₂)₄— M-2  Cl H H H HCOSMe —(CH₂)₄— M-3  Br H H H H COSMe —(CH₂)₄— M-4  Me H H H H COSMe—(CH₂)₄— M-5  Et H H H H COSMe —(CH₂)₄— M-6  Pr H H H H COSMe —(CH₂)₄—M-7  Bu H H H H COSMe —(CH₂)₄— M-8  Bu^(i) H H H H COSMe —(CH₂)₄— M-9 Bu^(t) H H H H COSMe —(CH₂)₄— M-10 OMe H H H H COSMe —(CH₂)₄— M-11 OEt HH H H COSMe —(CH₂)₄— M-12 OPr^(i) H H H H COSMe —(CH₂)₄— M-13 OPr H H HH COSMe —(CH₂)₄— M-14 OCHF₂ H H H H COSMe —(CH₂)₄— M-15 OCF₃ H H H HCOSMe —(CH₂)₄— M-16 CF₃ H H H H COSMe —(CH₂)₄— M-17 SMe H H H H COSMe—(CH₂)₄— M-18 SEt H H H H COSMe —(CH₂)₄— M-19 SPr^(i) H H H H COSMe—(CH₂)₄— M-20 NMe₂ H H H H COSMe —(CH₂)₄— M-21 NEt₂ H H H H COSMe—(CH₂)₄— M-22 H Cl H H H COSMe —(CH₂)₄— M-23 H Br H H H COSMe —(CH₂)₄—M-24 H Me H H H COSMe —(CH₂)₄— M-25 H Et H H H COSMe —(CH₂)₄—

TABLE 75

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-26 H Pr H H H COSMe —(CH₂)₄— M-27 H Pr^(i) H HH COSMe —(CH₂)₄— M-28 H Bu H H H COSMe —(CH₂)₄— M-29 H Bu^(i) H H HCOSMe —(CH₂)₄— M-30 H Bu^(s) H H H COSMe —(CH₂)₄— M-31 H Bu^(t) H H HCOSMe —(CH₂)₄— M-32 H OMe H H H COSMe —(CH₂)₄— M-33 H OEt H H H COSMe—(CH₂)₄— M-34 H OPr H H H COSMe —(CH₂)₄— M-35 H OPr^(i) H H H COSMe—(CH₂)₄— M-36 H OCHF₂ H H H COSMe —(CH₂)₄— M-37 H OCF₃ H H H COSMe—(CH₂)₄— M-38 H CF₃ H H H COSMe —(CH₂)₄— M-39 H SMe H H H COSMe —(CH₂)₄—M-40 H SEt H H H COSMe —(CH₂)₄— M-41 H SPr^(i) H H H COSMe —(CH₂)₄— M-42H NMe₂ H H H COSMe —(CH₂)₄— M-43 H NEt₂ H H H COSMe —(CH₂)₄— M-44 H H ClH H COSMe —(CH₂)₄— M-45 H H Br H H COSMe —(CH₂)₄— M-46 H H Me H H COSMe—(CH₂)₄— M-47 H H Et H H COSMe —(CH₂)₄— M-48 H H Pr H H COSMe —(CH₂)₄—M-49 H H Pr^(i) H H COSMe —(CH₂)₄— M-50 H H Bu H H COSMe —(CH₂)₄—

TABLE 76

R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ M-51 H H Bu^(i) H H COSMe —(CH₂)₄— M-52 H HBu^(s) H H COSMe —(CH₂)₄— M-53 H H Bu^(t) H H COSMe —(CH₂)₄— M-54 H HOMe H H COSMe —(CH₂)₄— M-55 H H OEt H H COSMe —(CH₂)₄— M-56 H H OPr H HCOSMe —(CH₂)₄— M-57 H H OPr^(i) H H COSMe —(CH₂)₄— M-58 H H OCHF₂ H HCOSMe —(CH₂)₄— M-59 H H OCF₃ H H COSMe —(CH₂)₄— M-60 H H CF₃ H H COSMe—(CH₂)₄— M-61 H H SMe H H COSMe —(CH₂)₄— M-62 H H SEt H H COSMe —(CH₂)₄—M-63 H H SPr^(i) H H COSMe —(CH₂)₄— M-64 H H NMe₂ H H COSMe —(CH₂)₄—M-65 H H NEt₂ H H COSMe —(CH₂)₄— M-66 Me NMe₂ H H H COSMe —(CH₂)₄— M-67NMe₂ Cl H H H COSMe —(CH₂)₄— M-68 Me NEt₂ H H H COSMe —(CH₂)₄— M-69 HNEt₂ Me H H COSMe —(CH₂)₄— M-70 Bu^(s) H H H H COSMe —(CH₂)₄— M-71Pr^(i) H H H H COSMe —(CH₂)₄— M-72 H OMe OMe H H COSMe —(CH₂)₄— M-73 HOMe OEt H H COSMe —(CH₂)₄— M-74 H OEt OMe H H COSMe —(CH₂)₄— M-75 H OEtOEt H H COSMe —(CH₂)₄—

TABLE 77

R¹ R² R³ n R⁶ R⁷ R⁸ R-1  H H H 1 CSSMe Me Me R-2  Cl H H 1 CSSMe Me MeR-3  Br H H 1 CSSMe Me Me R-4  Me H H 1 CSSMe Me Me R-5  Et H H 1 CSSMeMe Me R-6  Pr H H 1 CSSMe Me Me R-7  Bu H H 1 CSSMe Me Me R-8  Bu^(i) HH 1 CSSMe Me Me R-9  Bu^(t) H H 1 CSSMe Me Me R-10 Pr^(i) H H 1 CSSMe MeMe R-11 OEt H H 1 CSSMe Me Me R-12 OPr^(i) H H 1 CSSMe Me Me R-13 OPr HH 1 CSSMe Me Me R-14 OCHF₂ H H 1 CSSMe Me Me R-15 OCF₃ H H 1 CSSMe Me MeR-16 CF₃ H H 1 CSSMe Me Me R-17 SMe H H 1 CSSMe Me Me R-18 SEt H H 1CSSMe Me Me R-19 SPr^(i) H H 1 CSSMe Me Me R-20 NMe₂ H H 1 CSSMe Me MeR-21 NEt₂ H H 1 CSSMe Me Me R-22 H Cl H 1 CSSMe Me Me R-23 H Br H 1CSSMe Me Me R-24 H Me H 1 CSSMe Me Me R-25 H Et H 1 CSSMe Me Me

TABLE 78

R¹ R² R³ n R⁶ R⁷ R⁸ R-26 H Pr H 1 CSSMe Me Me R-27 H Pr^(i) H 1 CSSMe MeMe R-28 H Bu H 1 CSSMe Me Me R-29 H Bu^(i) H 1 CSSMe Me Me R-30 H Bu^(s)H 1 CSSMe Me Me R-31 H Bu^(t) H 1 CSSMe Me Me R-32 H OMe H 1 CSSMe Me MeR-33 H OEt H 1 CSSMe Me Me R-34 H OPr H 1 CSSMe Me Me R-35 H OPr^(i) H 1CSSMe Me Me R-36 H OCHF₂ H 1 CSSMe Me Me R-37 H OCF₃ H 1 CSSMe Me MeR-38 H CF₃ H 1 CSSMe Me Me R-39 H SMe H 1 CSSMe Me Me R-40 H SEt H 1CSSMe Me Me R-41 H SPr^(i) H 1 CSSMe Me Me R-42 H NMe₂ H 1 CSSMe Me MeR-43 H NEt₂ H 1 CSSMe Me Me R-44 Cl H Cl 1 CSSMe Me Me R-45 H H Br 1CSSMe Me Me R-46 H H Me 1 CSSMe Me Me R-47 H H Et 1 CSSMe Me Me R-48 H HPr 1 CSSMe Me Me R-49 H H Pr^(i) 1 CSSMe Me Me R-50 H H Bu 1 CSSMe Me Me

TABLE 79

R¹ R² R³ n R⁶ R⁷ R⁸ R-51 H H Bu^(i) 1 CSSMe Me Me R-52 H H Bu^(s) 1CSSMe Me Me R-53 H H Bu^(t) 1 CSSMe Me Me R-54 H H OMe 1 CSSMe Me MeR-55 H H OEt 1 CSSMe Me Me R-56 H H OPr 1 CSSMe Me Me R-57 H H OPr^(i) 1CSSMe Me Me R-58 H H OCHF₂ 1 CSSMe Me Me R-59 H H OCF₃ 1 CSSMe Me MeR-60 H H CF₃ 1 CSSMe Me Me R-61 H H SMe 1 CSSMe Me Me R-62 H H SEt 1CSSMe Me Me R-63 H H SPr^(i) 1 CSSMe Me Me R-64 H H NMe₂ 1 CSSMe Me MeR-65 H H NEt₂ 1 CSSMe Me Me R-66 Me NMe₂ H 1 CSSMe Me Me R-67 NMe₂ Cl H1 CSSMe Me Me R-68 Me NEt₂ H 1 CSSMe Me Me R-69 H NEt₂ Me 1 CSSMe Me MeR-70 Bu^(s) H H 1 CSSMe Me Me R-71 OMe H OMe 1 CSSMe Me Me R-72 H OMeOMe 1 CSSMe Me Me R-73 H OMe OEt 1 CSSMe Me Me R-74 H OEt OMe 1 CSSMe MeMe R-75 H OEt OEt 1 CSSMe Me Me

TABLE 80

R¹ R² R³ n R⁶ R⁷ R⁸ O-1  H H H 2 CSSMe Me Me O-2  Cl H H 2 CSSMe Me MeO-3  Br H H 2 CSSMe Me Me O-4  Me H H 2 CSSMe Me Me O-5  Et H H 2 CSSMeMe Me O-6  Pr H H 2 CSSMe Me Me O-7  Bu H H 2 CSSMe Me Me O-8  Bu^(i) HH 2 CSSMe Me Me O-9  Bu^(t) H H 2 CSSMe Me Me O-10 Pr^(i) H H 2 CSSMe MeMe O-11 OEt H H 2 CSSMe Me Me O-12 OPr^(i) H H 2 CSSMe Me Me O-13 OPr HH 2 CSSMe Me Me O-14 OCHF₂ H H 2 CSSMe Me Me O-15 OCF₃ H H 2 CSSMe Me MeO-16 CF₃ H H 2 CSSMe Me Me O-17 SMe H H 2 CSSMe Me Me O-18 SEt H H 2CSSMe Me Me O-19 SPr^(i) H H 2 CSSMe Me Me O-20 NMe₂ H H 2 CSSMe Me MeO-21 NEt₂ H H 2 CSSMe Me Me O-22 H Cl H 2 CSSMe Me Me O-23 H Br H 2CSSMe Me Me O-24 H Me H 2 CSSMe Me Me O-25 H Et H 2 CSSMe Me Me

TABLE 81

R¹ R² R³ m R⁶ R⁷ R⁸ O-26 H Pr H 2 CSSMe Me Me O-27 H Pr^(i) H 2 CSSMe MeMe O-28 H Bu H 2 CSSMe Me Me O-29 H Bu^(i) H 2 CSSMe Me Me O-30 H Bu^(s)H 2 CSSMe Me Me O-31 H Bu^(t) H 2 CSSMe Me Me O-32 H OMe H 2 CSSMe Me MeO-33 H OEt H 2 CSSMe Me Me O-34 H OPr H 2 CSSMe Me Me O-35 H OPr^(i) H 2CSSMe Me Me O-36 H OCHF₂ H 2 CSSMe Me Me O-37 H OCF₃ H 2 CSSMe Me MeO-38 H CF₃ H 2 CSSMe Me Me O-39 H SMe H 2 CSSMe Me Me O-40 H SEt H 2CSSMe Me Me O-41 H SPr^(i) H 2 CSSMe Me Me O-42 H NMe₂ H 2 CSSMe Me MeO-43 H NEt₂ H 2 CSSMe Me Me O-44 F H F 2 CSSMe Me Me O-45 H H Br 2 CSSMeMe Me O-46 H H Me 2 CSSMe Me Me O-47 H H Et 2 CSSMe Me Me O-48 H H Pr 2CSSMe Me Me O-49 H H Pr^(i) 2 CSSMe Me Me O-50 H H Bu 2 CSSMe Me Me

TABLE 82

R¹ R² R³ n R⁶ R⁷ R⁸ O-51 H H Bu^(i) 2 CSSMe Me Me O-52 H H Bu^(s) 2CSSMe Me Me O-53 H H Bu^(t) 2 CSSMe Me Me O-54 H H OMe 2 CSSMe Me MeO-55 H H OEt 2 CSSMe Me Me O-56 H H OPr 2 CSSMe Me Me O-57 H H OPr^(i) 2CSSMe Me Me O-58 H H OCHF₂ 2 CSSMe Me Me O-59 H H OCF₃ 2 CSSMe Me MeO-60 H H CF₃ 2 CSSMe Me Me O-61 H H SMe 2 CSSMe Me Me O-62 H H SEt 2CSSMe Me Me O-63 H H SPr^(i) 2 CSSMe Me Me O-64 H H NMe₂ 2 CSSMe Me MeO-65 H H NEt₂ 2 CSSMe Me Me O-66 Me NMe₂ H 2 CSSMe Me Me O-67 NMe₂ Cl H2 CSSMe Me Me O-68 Me NEt₂ H 2 CSSMe Me Me O-69 H NEt₂ Me 2 CSSMe Me MeO-70 Bu^(s) H H 2 CSSMe Me Me O-71 OMe H OMe 2 CSSMe Me Me O-72 H OMeOMe 2 CSSMe Me Me O-73 H OMe OEt 2 CSSMe Me Me O-74 H OEt OMe 2 CSSMe MeMe O-75 H OEt OEt 2 CSSMe Me Me

TABLE 83

R¹ R² R³ n R⁶ R⁷ R⁸ P-1  H H H 1 CSSMe Et Et P-2  Cl H H 1 CSSMe Et EtP-3  Br H H 1 CSSMe Et Et P-4  Me H H 1 CSSMe Et Et P-5  Et H H 1 CSSMeEt Et P-6  Pr H H 1 CSSMe Et Et P-7  Bu H H 1 CSSMe Et Et P-8  Bu^(i) HH 1 CSSMe Et Et P-9  Bu^(t) H H 1 CSSMe Et Et P-10 Pr^(i) H H 1 CSSMe EtEt P-11 OEt H H 1 CSSMe Et Et P-12 OPr^(i) H H 1 CSSMe Et Et P-13 OPr HH 1 CSSMe Et Et P-14 OCHF₂ H H 1 CSSMe Et Et P-15 OCF₃ H H 1 CSSMe Et EtP-16 CF₃ H H 1 CSSMe Et Et P-17 SMe H H 1 CSSMe Et Et P-18 SEt H H 1CSSMe Et Et P-19 SPr^(i) H H 1 CSSMe Et Et P-20 NMe₂ H H 1 CSSMe Et EtP-21 NEt₂ H H 1 CSSMe Et Et P-22 H Cl H 1 CSSMe Et Et P-23 H Br H 1CSSMe Et Et P-24 H Me H 1 CSSMe Et Et P-25 H Et H 1 CSSMe Et Et

TABLE 84

R¹ R² R³ n R⁶ R⁷ R⁸ P-26 H Pr H 1 CSSMe Et Et P-27 H Pr^(i) H 1 CSSMe EtEt P-28 H Bu H 1 CSSMe Et Et P-29 H Bu^(i) H 1 CSSMe Et Et P-30 H Bu^(s)H 1 CSSMe Et Et P-31 H Bu^(t) H 1 CSSMe Et Et P-32 H OMe H 1 CSSMe Et EtP-33 H OEt H 1 CSSMe Et Et P-34 H OPr H 1 CSSMe Et Et P-35 H OPr^(i) H 1CSSMe Et Et P-36 H OCHF₂ H 1 CSSMe Et Et P-37 H OCF₃ H 1 CSSMe Et EtP-38 H CF₃ H 1 CSSMe Et Et P-39 H SMe H 1 CSSMe Et Et P-40 H SEt H 1CSSMe Et Et P-41 H SPr^(i) H 1 CSSMe Et Et P-42 H NMe₂ H 1 CSSMe Et EtP-43 H NEt₂ H 1 CSSMe Et Et P-44 OMe H H 1 CSSMe Et Et P-45 H H Br 1CSSMe Et Et P-46 H H Me 1 CSSMe Et Et P-47 H H Et 1 CSSMe Et Et P-48 H HPr 1 CSSMe Et Et P-49 H H Pr^(i) 1 CSSMe Et Et P-50 H H Bu 1 CSSMe Et Et

TABLE 85

R¹ R² R³ n R⁶ R⁷ R⁸ P-51 H H Bu^(i) 1 CSSMe Et Et P-52 H H Bu^(s) 1CSSMe Et Et P-53 H H Bu^(t) 1 CSSMe Et Et P-54 H H OMe 1 CSSMe Et EtP-55 H H OEt 1 CSSMe Et Et P-56 H H OPr 1 CSSMe Et Et P-57 H H OPr^(i) 1CSSMe Et Et P-58 H H OCHF₂ 1 CSSMe Et Et P-59 H H OCF₃ 1 CSSMe Et EtP-60 H H CF₃ 1 CSSMe Et Et P-61 H H SMe 1 CSSMe Et Et P-62 H H SEt 1CSSMe Et Et P-63 H H SPr^(i) 1 CSSMe Et Et P-64 H H NMe₂ 1 CSSMe Et EtP-65 H H NEt₂ 1 CSSMe Et Et P-66 Me NMe₂ H 1 CSSMe Et Et P-67 NMe₂ Cl H1 CSSMe Et Et P-68 Me NEt₂ H 1 CSSMe Et Et P-69 H NEt₂ Me 1 CSSMe Et EtP-70 Bu^(s) H H 1 CSSMe Et Et P-71 OMe H OMe 1 CSSMe Et Et P-72 H OMeOMe 1 CSSMe Et Et P-73 H OMe OEt 1 CSSMe Et Et P-74 H OEt OMe 1 CSSMe EtEt P-75 H OEt OEt 1 CSSMe Et Et

TABLE 86

R¹ R² R³ n R⁶ R⁷ R⁸ Q-1  H H H 2 CSSMe Et Et Q-2  Cl H H 2 CSSMe Et EtQ-3  Br H H 2 CSSMe Et Et Q-4  Me H H 2 CSSMe Et Et Q-5  Et H H 2 CSSMeEt Et Q-6  Pr H H 2 CSSMe Et Et Q-7  Bu H H 2 CSSMe Et Et Q-8  Bu^(i) HH 2 CSSMe Et Et Q-9  Bu^(t) H H 2 CSSMe Et Et Q-10 Pr^(i) H H 2 CSSMe EtEt Q-11 OEt H H 2 CSSMe Et Et Q-12 OPr^(i) H H 2 CSSMe Et Et Q-13 OPr HH 2 CSSMe Et Et Q-14 OCHF₂ H H 2 CSSMe Et Et Q-15 OCF₃ H H 2 CSSMe Et EtQ-16 CF₃ H H 2 CSSMe Et Et Q-17 SMe H H 2 CSSMe Et Et Q-18 SEt H H 2CSSMe Et Et Q-19 SPr^(i) H H 2 CSSMe Et Et Q-20 NMe₂ H H 2 CSSMe Et EtQ-21 NEt₂ H H 2 CSSMe Et Et Q-22 H Cl H 2 CSSMe Et Et Q-23 H Br H 2CSSMe Et Et Q-24 H Me H 2 CSSMe Et Et Q-25 H Et H 2 CSSMe Et Et

TABLE 87

R¹ R² R³ m R⁶ R⁷ R⁸ Q-26 H Pr H 2 CSSMe Et Et Q-27 H Pr^(i) H 2 CSSMe EtEt Q-28 H Bu H 2 CSSMe Et Et Q-29 H Bu^(i) H 2 CSSMe Et Et Q-30 H Bu^(s)H 2 CSSMe Et Et Q-31 H Bu^(t) H 2 CSSMe Et Et Q-32 H OMe H 2 CSSMe Et EtQ-33 H OEt H 2 CSSMe Et Et Q-34 H OPr H 2 CSSMe Et Et Q-35 H OPr^(i) H 2CSSMe Et Et Q-36 H OCHF₂ H 2 CSSMe Et Et Q-37 H OCF₃ H 2 CSSMe Et EtQ-38 H CF₃ H 2 CSSMe Et Et Q-39 H SMe H 2 CSSMe Et Et Q-40 H SEt H 2CSSMe Et Et Q-41 H SPr^(i) H 2 CSSMe Et Et Q-42 H NMe₂ H 2 CSSMe Et EtQ-43 H NEt₂ H 2 CSSMe Et Et Q-44 OMe H H 2 CSSMe Et Et Q-45 H H Br 2CSSMe Et Et Q-46 H H Me 2 CSSMe Et Et Q-47 H H Et 2 CSSMe Et Et Q-48 H HPr 2 CSSMe Et Et Q-49 H H Pr^(i) 2 CSSMe Et Et Q-50 H H Bu 2 CSSMe Et Et

TABLE 88

R¹ R² R³ n R⁶ R⁷ R⁸ Q-51 H H Bu^(i) 2 CSSMe Et Et Q-52 H H Bu^(s) 2CSSMe Et Et Q-53 H H Bu^(t) 2 CSSMe Et Et Q-54 H H OMe 2 CSSMe Et EtQ-55 H H OEt 2 CSSMe Et Et Q-56 H H OPr 2 CSSMe Et Et Q-57 H H OPr^(i) 2CSSMe Et Et Q-58 H H OCHF₂ 2 CSSMe Et Et Q-59 H H OCF₃ 2 CSSMe Et EtQ-60 H H CF₃ 2 CSSMe Et Et Q-61 H H SMe 2 CSSMe Et Et Q-62 H H SEt 2CSSMe Et Et Q-63 H H SPr^(i) 2 CSSMe Et Et Q-64 H H NMe₂ 2 CSSMe Et EtQ-65 H H NEt₂ 2 CSSMe Et Et Q-66 Me NMe₂ H 2 CSSMe Et Et Q-67 NMe₂ Cl H2 CSSMe Et Et Q-68 Me NEt₂ H 2 CSSMe Et Et Q-69 H NEt₂ Me 2 CSSMe Et EtQ-70 Bu^(s) H H 2 CSSMe Et Et Q-71 OMe H OMe 2 CSSMe Et Et Q-72 H OMeOMe 2 CSSMe Et Et Q-73 H OMe OEt 2 CSSMe Et Et Q-74 H OEt OMe 2 CSSMe EtEt Q-75 H OEt OEt 2 CSSMe Et Et

The above compounds of the present invention were examined as shownbelow.

Example 1 Experiments for Human CB2 Receptor (CB2R) Binding Inhibition

The coding region of human CB2R cDNA (Munro etc, Nature, 1993, 365,61–65) was inserted into the mammalian expression vector, pSVL SV40 LatePromoter Expression Vector (Amersham Pharmacia Biotech Inc.). Theprepared vector was transfected into Chinese Hamster Ovary (CHO) cellswith LipofectAMINE reagent (Gibco BRL) according to the manufacture'sprotocol, and the stable CB2R-expressing clones were selected.

The crude membrane fractions were then prepared from the CB2R-expressingCHO cells. Receptor binding assay was performed by incubating themembranes with each test compound and [³H]CP55940 (at a finalconcentration of 0.5 nM: NEN Life Science Products) in the assay buffer(50 mM Tris-HCl, 1 mM EDTA, 3 mM MgCl₂, pH 7.4) containing 0.5% bovineserum albumin (BSA) for 2 hr at 25° C. The incubation mixture wasfiltered through 1% polyethylenimine (PEI)-treated GF/C glass filter andwashed with 50 mM Tris-HCl (pH 7.4) containing 0.1% BSA. Theradioactivity was then counted with a liquid scintillation counter.Nonspecific binding was determined in the presence of 10 μM WIN55212-2(a CB agonist described in the patent U.S. Pat. No. 508,122, ResearchBiochemicals International), and the specific binding was calculated bysubtracting the nonspecific binding from the total binding. The IC₅₀value for each test compound was determined as the concentration atwhich 50% of the specific binding was inhibited.

For the receptor binding assay of human CB1 receptor (CB1R), the stableCB1R-expressing CHO cells were prepared as described above, and thebinding assay was performed with their membrane fractions. As aconsequence of these studies, the Ki values of each test compound forboth cannabinoid receptors were determined, which were presented inTable 89. As shown in this table, a series of compounds described in thepresent invention were found to selectively block the binding of CP55940(a CB agonist described in the patent U.S. Pat. No. 4,371,720) to CB2Rmore effectively than CB1R.

TABLE 89 Compound Ki (nM) No. CB1 receptor CB2 receptor I-5 >5000 61I-23 >5000 29 I-50 >5000 39 I-51 n.t. 23 I-52 n.t. 35 I-56 n.t. 54I-6 >5000 9 I-57 4134 6 I-69 n.t. 33 I-60 2097 18 I-62 n.t. 44 I-63 n.t.43 I-74 n.t. 48 I-77 n.t. 53 I-84 >5000 35 I-85 n.t. 25 n.t.: not tested

Example 2 Inhibition Experiments for CB2R-Mediated Suppression of cAMPSynthesis

The CHO cells expressing human CB2R were incubated with test compoundsfor 15 min. After the incubation, 4 μM forskolin (Sigma) was added andthe cells were incubated for 20 min at 37° C. The reaction was stoppedby the addition of 1N HCl and the amount of cAMP in the cell supernatantwas measured using an EIA kit (Amersham Pharmacia Biotech) according tothe manufacture's protocol. The cAMP amount increased by forskolincompared to that in the absence of forskolin was defined as 100%, andthe IC₅₀ value of each test compound was determined as the concentrationat which 50% of the forskolin-stimulated cAMP synthesis was inhibited.As a consequence of these studies, the IC₅₀ value of each test compoundwas presented in Table 90. As shown in Table 90, the compounds describedin the present invention were found to possess agonistic activity towardCB2R.

The antagonistic activity of each compound was also evaluated in thisassay.

TABLE 90 Compound No. IC₅₀ (nM) I-5 6.5 I-23 2.6 I-51 2.8 I-6 2.7 I-575.5

Example 3 Experiments for Sheep Red Blood Cell (SRBC)-induced DelayedType Hypersensitive (DTH) Reaction

Female ddY mice (7 weeks old) were used for the sheep red blood cell(SRBC)-induced delayed type hypersensitive (DTH) reaction.

Cannabinoid receptor agonist, I-6, I-60, I-77 and I-118 were suspendedin 0.6% arabic gum solution. Mice were sensitized by the intradermalinjection of 10⁷ cells of SRBC (40 μl/foot) into the left hind foot pad.After 5 days, DTH reaction was induced by the intradermal injection of10⁸ cells of SRBC in the right hind foot pad. Test compounds wereadministerd p.o. (10 ml/kg) 1 hr before and 5 hr after the induction ofDTH reaction. After 24 hrs of the injection of SRBC, the left and rightfoot pad volumes were measured by the water displacement method. Thefoot pad swelling was calculated as the differences in the volumesbetween the right and left hind foot pad, and used as an index of theDTH reaction.

Data are expressed as the inhibition percentage of each compound.Statistical analysis was performed with Welch's t-test, in which thevalue of P<0.05 is considered as a significant difference.

TABLE 91 Comp. Inhibition No. Dose (mg/kg) percentage (%) I-6 40 45.2I-6O 30 31.1 I-77 30 33.8 I-118 30 33.0

INDUSTRIAL APPLICABILITY

The compound of the formula (I) and (II) of the present inventionselectively binds to the cannabinoid type 2 receptor (CB2R) to exhibitan antagonistic activity or agonistic activity to CB2R. Therefore, thepresent compound neither causes side effects on the central nervoussystem such as illusion or the drug dependence associated with thecannabinoid type 1 receptor (CB1R) and can be used for treating orpreventing diseases associated with the cannabinoid type 2 receptor(CB2R).

1. A pharmaceutical composition comprising a compound of the formula(I):

wherein R¹ is optionally substituted alkylene, R² is alkyl; a group ofthe formula: —C(═R⁵)—R⁶ wherein R⁵ is O or S, R⁶ is alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substitutedaralkyloxy, optionally substituted aralkylthio, optionally substitutedaralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substitutedaminoalkyl; or a group of the formula: —SO₂R⁷ wherein R⁷ is alkyl,optionally substituted amino, optionally substituted aryl or optionallysubstituted heteroaryl, m is an integer of 1 to 2, A is optionallysubstituted aromatic carbocycle or optionally substituted aromaticheterocycle, a prodrug thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 2. The pharmaceutical compositionaccording to claim 1 wherein the group of the formula:

is a group of the formula:

wherein R³ and R⁴ each is independently, hydrogen, alkyl, alkoxy,alkylthio, optionally substituted amino, optionally substituted aryl,optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro,haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy,alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl,alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy,alkylthioalkoxy, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, alkoxyiminoalkyl or a groupof the formula: —C(═O)—R^(H) wherein R^(H) is hydrogen, alkyl,optionally substituted aryl or optionally substituted non-aromaticheterocyclic group, or R³ and R⁴ taken together may form alkylenedioxy,A is optionally substituted aromatic carbocycle or optionallysubstituted aromatic heterocycle.
 3. The pharmaceutical compositionaccording to claim 1 which has a binding activity to a cannabinoid type2 receptor.
 4. The pharmaceutical composition according to claim 3 whichhas an agonistic activity to a cannabinoid type 2 receptor.
 5. Thepharmaceutical composition according to claim 3 which is useful as ananti-inflammatory agent.
 6. The pharmaceutical composition according toclaim 3 which is useful as an immunosuppressive agent.
 7. Thepharmaceutical composition according to claim 3 which is useful as anephritis treating agent.
 8. A method for treating inflammation whichcomprises administering the pharmaceutical composition according toclaim 1 to a patient in need thereof.
 9. A method of immunosuppressionwhich comprises administering the pharmaceutical composition accordingto claim 1 to a patient in need thereof.
 10. A method for treatingnephritis which comprises administering the pharmaceutical compositionaccording to claim 1 to a patient in need thereof.